Delta and delta1,4 derivatives of 16alpha-fluorosteroid-[3, 2-c] pyrazoles of the pregnane series



United States Patent 3,116,287 A AND A DERIVATIVES OF 16a-FLUORO- STEROID-[3,2-c1PYRAZOLES OF THE PREG- NANE SERIES Ralph F. Hirschmann, Scotch Plains, and Arthur A. Patchett, Metuchen, NJ., assignors to Merck & Co., Inc., Rahway, NJ., a corporation of New Jersey No Drawing. Filed June 20, 1962, Ser. No. 203,713 Claims. (Cl. 260--239.8)

This invention is concerned generally with novel 4- pregnenoand 4,6-pregnadieno-[3,2-c1pyrazole compounds, and with processes of preparing the same. More particularly, it relates to novel IGa-flllOIO-l7oc-hYdIOXY-20- oXo-4-pregnenoand 4,6-pregnadieno-[3,2-c1pyrazole compounds and to processes of making these compounds starting from the corresponding 16ec-fillOIO-170L,Zl-dihydroxy-4-pregneneand 4,6-pregnadiene 3,20-dione.

These novel steroids may be chemically represented by structures A and B and the analogous M' -structures.

wherein R is [i-halogen, fi-hydroxy or keto, but ii-halogen is present at R only when X is halogen, R is halogen, hydrogen or methyl, R is hydrogen, hydroxy, acyloxy or fiuoro, R is hydrogen, acyl, alkyl, cycloalkyl, aralkyl, aryl, a hete-rocyclic nucleus or substituted derivatives thereof, and X is hydrogen or halogen, and wherein any acyl group present as an acyloxy group at R may be the same or dilferent from any acyl group present at R N-substituted-pyrazole compounds having structure A are herein designated as the l-substituted [3,2-c1pyrazoles, and N-substituted-pyrazole compounds having structure B are designated as the 2'-substituted-[3,2-c] pyrazoles.

The above defined [3,2-c]pyrazoles produced in accordance with the present invention possess high antiinflammatory activity, and are especially effective for the treatment of arthritis and related diseases since they can be administered for their cortisone-like action in low dosage thereby minimizing undesirable side elfects.

In preparing our novel chemical compounds, the starting material utilized is a lGot-fluoro-l7a,2l-dihydroxy-4- 3,115,287 Patented Dec. 31, 1963 pregnene-3,20-dione which may be identified by the following structural formula:

CHzOH A-D and in Examples 9-21.

The starting materials defined above will react with aqueous formaldehyde solutions in the presence of strong acid to form compounds having the formula:

or the A -analogues of compounds having the above structure, wherein R R and X have the significance above defined. For example, cold, concentrated HCl and formalin are added to a stirred suspension of the steroid in chloroform, cooled to about 0 C. The mixture is then allowed to come to room tempera-ture and stirred for several hours to afford the corresponding 17 11,20,2031-bis(methylenedioxy) -derivative.

Compare also Flow Sheet B, Compound 14 which the A -17a,20,20,21 bis(methylenedioxy) compounds are prepared by the action of chloranil on the corresponding M-compounds.

In a preferred embodiment of our invention, the 17a,20,20,2l bis(methylenedioxy) compound which has the following formula:

or the A -analogue of a compound having the above structure, wherein R and X halve the significance above defined, is prepared by oxidation of the corresponding 11,3 hydroxy 17a,20,20,21 bis(methylenedioxy)- compound, for example, with chromium trioxide in a non-aqueous base such as pyridine. If desired, however, the 17a,20,20,2 1-bis( methylenedioxy l 6u-fluoro-4-preg- Ilene-(or :4,6-pregnadiene)-3,ll-dione may' be prepared directly by the reaction of the l6u-fluoro-l7a,2l-dihydroxy-4-pregnene-(or 4,6-pregdiene)-3,11,20-trione with formaldehyde solution in the presence of an acid as described in the preceding step.

Upon treatment of the l7a,20,20,2l-bis-(methylenedioxy)-compound with an alkyl formate and sodium hydride in an inert atmosphere there is formed the corresponding Z-hydroxymethylene derivative which has the following structure, or the A -analogue of a compound having the following structure:

wherein R is fi-halogen, fl-hydroxy and/ or ,H-formyloXy-, or keto-, but fi-halogen is present at R only when X is halogen, and R and X have the significance above defined. In a preferred embodiment of our invention, the steroid is dissolved in a solvent such as benzene and the resulting solution is cooled to room temperature and treated with ethyl formate. The air in the system is replaced with nitrogen, sodium hydride is added and the mixture is stirred at room temperature for several hours.

The 17a,2(),20,21-bi$ (methylenedioxy) -16a-fluoro-2-hydroxymethylene-4-pregnene-(or 4,6-pregnadiene)-3 one reacts with hydrazine in an inert atmosphere to form the corresponding 4-pregneno-(or 4,6-pregnadieno)-[3,2-c] pyrazole.

Upon treatment of a 17 u,20,20,2.l-bis-(methylenedioxy)- 16a-fluoro-2-hydroxymethylene-4-pregnene-(or 4,6-pregnadiene)-3-one with a lower alkanol in the presence of an acidic reagent such as a p-toluenesulfonic acid the corresponding 2-alkoxymethylene-derivative is formed. When the latter compound is reacted with a monosubstituted hydrazine, the corresponding N-substituted-[3,2-c] pyrazole compounds are formed. The N-substituted- [3,2-c]pyrazoles having structure A are designated as the 1-substituted-[3,2-c]pyrazoles, and the N-substitutedpyrazole compounds having structure B are designated as the 2'-substituted-[3,2-c] pyrazoles. The corresponding A -St6I'0idS' are similarly designated. R R and X have the significance above defined, and R is heterocyclic alkyl, cycloalkyl, aralkyl or an aryl group. The products formed may be separated by chromatography.

Upon treatment of a 17a,20,20,2l-bis-(methylenedioxy)-16u-fluoro-2-hydroxymethylene-4-pregnene-(or 4, 6-pregnadiene)-3-one compound directly with a monosubstituted arylhydrazine, without the intermediate formation of the 2-alkoxymethylene-derivative, one isomer is generally formed in preponderant amounts, whereas when reacting the 2-alkoxymethy1ene compound with a monosubstituted arylhydrazine, significant amounts of both isomers are obtained. When these reactions take place with monosubstituted alkylhydrazines, mixtures may be obtained when starting with the 2-hydroxymethylenesteroid as Well as with the 2-alkoxymethylene-steroid. A mixture of isomers may also result from the reaction of a monosubstituted hydrazine with a Z-hydroxymethylenecompound which possibly contains variable amounts of the 2-alkoxymethylene-derivative due to the operating procedures employed, for example, due to recrystallization in the presence of alcohol a solution of the 2-hydroxymethylene-compound from which acid has not been completely removed.

Among the monosubstituted hydrazines which may he used for the process of our invention are: alkylhydrazines, such as methylhydrazine, ethylhydrazine, propylhydrazines, lbutylhydrazines, 3-hydroxyethylhydrazine, cycloalkylhydrazines; arylhydrazines including phenylhydrazine and the substituted phenylhydrazines, such as o-, m-, and p-h-alophenylhydrazines, o-, m-, and p-tolylhydrazines, o-, m-, and p-alkoxyphenylhydrazines, 0-, m-, and p-nitrophenylhydrazines, l-hydrazinonaphthalene, Z-hydrazinopyridine, 3-hydrazinopyridine, 4-hydrazinopyridine, 4- hydrazinopyridine oxide, 2-hydrazinopyrimidine; 2-hydrazinothiophene and S-hydrazinothiophene; aralkylhydrazines, such as benzylhydrazine and phenylethylenehydrazine.

There are thus produced the corresponding N-substituted-4-pregneno-[3,2-c]pyrazoles including: N- alkyl such as N-methyl-, N-ethyl-, N-butyl-, N-propyl-, N-(flhydroXyethyl-)-; N-cycloalkyl-; N-arylwhich maybe derived from any aromatic nucleus, including N-phenyland the N-substituted-phenyl derivatives such as o-, m-, and p-halophenyl; 0-, m-, and p-tolyl-; o-, m-, and p-alkoxyphenyl-, o-, m-, and p-nitrophenyl-; N-(1"-naphthyl)-, N- "-PY Y "-Py y "-PY Y pyridyloxide)-, N-(2"-pyrimidyl)-, N-(2"-thiophene)- and N-(3-thiophene)-: N-aralkyl-, such as N-benzyland N-phenylethenyl- 3,2-c] pyrazoles.

The N-alkyl- [3,2-c1pyrazoles may also be prepared by direct alkylation of the N-unsubstituted 4-pregneno-[3,2- c] pyrazoles.

A 17a,20,20,21-bis(methylenedioxy)-16a-fluoro 11,3- hydroxy-4-pregneno- (or 4,6-pregnadieno) 3,2-c]pyrazoles which have a 9u-halo-substituent are preferably prepared by the following alternate route.

Using the procedures described above, the 9a-halo- 16a-fiuoro-115,17a,21 trihydroxy-4-pregnene-(or 4,6- pregnadiene)-3,20-dione is converted into the corresponding 1700,20,2O,21 -bis(methylenedioxy) derivative. The latter compound is then oxidized to the 17a,20,20,21-bi$ (methylenedioxy) -16a-fluoro-9a-halo-4-pregnene- (or 4, 6- pregnadiene)-3,11-dione, which is reacted with ethyl formate and sodium hydride to form the Z-hydroxymethylenederivative. The latter compound is reacted with hydrazine, or a mono-substituted hydrazine, to give the corresponding 17a,20,20,21-bis(methylenedioxy) 16OL-fill0l'0- 9a-halo-1 1-oxo-4-pregneno- (or 4,6-pregnadieno)-[3,2-c] pyrazole compound, or the N-substituted derivative there of. The latter compound is then reduced to the corresponding 11 I3-l1YdIOXY-d61iVflfiV6, for example, by adding a saturated solution of sodium borohydride to a solution of the steroid in a mixture of triethylamine and isopropyl alcohol to which we prefer to add a little water, and allowing the mixture to stand over night. (Compare EX- ample 5.)

Upon treatment of any of the above described 17a, 20, 20,2l-o=is(methylenedioxy)-compounds with a dilute organic acid, for example, a 60% aqueous solution of formic acid, the l7a,20,20,2 1-bis(methylenedioxy)protecting group is removed and there is obtained the corresponding 16a-fiuoiro-170,21-dihydroxy-2O-oxo-4-pregneno- [3,2-c]pyrazoles which are represented by structures A and B, and the N -analogues thereof.

CH1O Ra wherein R is fl-halogen, fl-hydroxy or keto, but fi-halogen is present at R only when X is halogen; R and X have the meaning described above and wherein R is acyl, alkyl, cycloalkyl, aryl, aralkyl, a heterocyclic nucleus, or substituted derivatives thereof, and R is hydrogen, an acyl group corresponding to the organic acid used in this reaction, or a mixture of the two.

Any acyl groups present at R and/or at R; may be removed by treating the steroid with sodium methoxide in methanol at room temperature to form the corresponding 16a-fluoro-17a,2l-dihydroxy 20 oxo-4-pregneno-(or 4,6-pregnadieno) -[3,2-e]-pyrazole. Acyl groups present at the R position may be selectively removed by treatment with aqueous acetic acid.

The compounds of our invention include, among others, the following:

16u-fluoro l 1p, 1 7oc,2 l-trihydroxy-6-methyl-20-oxo-2'- phenyl-4, 6-pregnadieno- 3 ,2-c] pyrazole,

6, 16a-difluoro-1 1/3,17a,21-tnihydroxy-20oxo-2'-phenyl- 4,6 pregnadieno- 3 ,2-c] pyrazole,

6-ch1oro-1 6a-fluoro-1 1B, 17,2 1 -trihydroxy-20-oxo-2- phenyl-4, 6-plregnadieno- [3, 2-c] pyrazole,

911,1 1B-dichloro-6,l6a-difluoro-21-hydroxy-20-oxo- 4,6 pregneno- 3,2-c] pyrazole,

as well as the 1- and 2'-alkyl-, the 1'- and 2'-cycloalkyl-,

the 1'- and 2'-aryl, and the 1'- and 2-ara'lkylderivatives of all of the above named compounds.

The 21-acyl derivatives of the above described 16afluoro-17a,21-dihydroxy-20-oxo-4-pregneno-(or 4,6-pregnadieno)-[3,2-c]-pyrazoles in which R; is H may be prepared by heating an N-acyl-l 6a-fiuoro-l7 2l-dihydroxy- 20-oxo-4-pregneno-(or 4,6-pregnadieno)-[3,2-c]pyrazole 21-acylate with aqueous acetic acid, whereupon the N-acyl group is selectively removed.

The N-acyl-2l-acylate derivatives of the above described 16a-fluoro-l7a,21-dihydroxy-20-oxo-4-pregneno- (or 4,6-pregnadieno)-[3,2-c]pyrazoles in which both acyl groups are the same may be prepared by reacting a 160:- fluoro-l7a,21-dihydroxy-20-oxo-4-pregneno-(or 4,6-pregnadieno)-[3,2-c]pyrazole with two equivalents of an acylating agent.

The N-acyl-Zl-acylate derivatives of the above described 16a-fluoro-17a,21-dihydroXy-20-oxo-4-pregneno- (or 4,6-pregnadieno)-[3,2-c]pyrazoles in which the acyl groups are difierent are prepared by reaction of 16afluoro-l701,21-dihydroxy-20-oxo-4-pregneno-(or 4,6-pregnadieno)-[3,2-c]pyrazo1e 21-acylate with an acylating agent in which the acyl group of the acylating agent is diiferent from the acyl group already present at the 21- position of the pyrazole.

Acylating agents which can be used for this purpose include a lower hydrocarbon carboxylic acid acylating agent such as benzoic anhydride, or tertiary butyl acetyl chloride; a lower alkanoic anhydn'de or lower alkanoyl halide such as acetic anhydride, propionic anhydrides or acetyl chloride; or a polybasic anhydride such as fifi-dimethylglutaric anhydride, succinic anhydride and the like, in the presence of an organic base such as pyridine.

The- 160: fluoro-17a,21-dihydroxy-20-oxo-4-pregneno- (or 4,6 pregnadieno)-[3,2 c]pyrazo1e is reacted with methane sulfonyl chloride in a nonaqueous base to form the 21-mesylate. A steroid in which R; is hydrogen is first converted to the N-carbamyl-derivative before undergoing this reaction.

The fluoro-l7a,21-dihydroxy-ZO-oxo-4-pregneno- (or 4,6-pregnadieno) [3,2 c]pyrazole 21-mesylate is heated with an alkali iodide to form the 2l-iodo-compound. In a preferred method for carrying out this reaction, sodium iodide is added to the steroid dissolved in acetone and the resulting mixture is heated at reflux temperature for approximately one hour.

The 16a-fiuoro-17whydroxy-2l-iodo 20 oxo-4-pregneno-(or 4,6-pregnadieno)-[3,2-c1pyrazole is heated with an alkali bisulfite in a solvent to form the corresponding 21-desoxy-compound which has structure A or B, wherein R is carbamyl, or alkyl, cycloalkyl, aralkyl, aryl, a heterocyclic nucleus or substituted derivatives thereof,

wherein R R and X have the significance above defined. A preferred method is to add sodium bisulfite to a suspension of the steroid in aqueous ethanol and then heat the mixture under reflux for a period of about an hour.

Any carbamyl group present at R.,, may be removed by treating the steroid in glacial acetic acid with sodium nitrite.

Thus the novel compounds of our invention which are formed from the above reactions include:

wherein R R R and X have the significance above described.

All of the [3,2-c1pyrazoles described in the foregoing structures form salts such as the hydrochloride, sulfate, chlorate, perchlorate, picrate and trichloroacetate, on treatment with the corresponding acid. Formation of crystalline salts, especially the hydrochloride salts, provides a means of isolating the [3,2-c]pyrazoles.

A further embodiment of our invention comprises novel pharmaceutical compositions containing the novel [3,2-c] pyrazoles exemplified in the foregoing structures.

The 17m-acetox-y-9a,1 1 fl-diChlOFO-16oc-fillOIO-20-OXO-4- pregneno-(or 4,6-pregnadieno)-[3,2-c]pyrazoles are prepared from the 17a-hydroXy-9a,11/3-dichloro-1=6a-fluoro- 20-oxo-4-pregnen0- (or 4,6-pregnadieno) [3,2-c]pyrazo1es by reacting first with acetic anhydride and p-toluenesulfonic acid to form the N-acetyl-Zl-acetate and then treating with methanolic sodium hydroxide to remove the N- acetate group. (Compare Example 22.)

Methods for the preparation of the starting materials used in the process of our invention are outlined in Flow Sheets A to D, detailed procedures for which are included in Examples 9 through 21.

STARTING MATERIALS FLOW SHEET A 1 ICE ai 3 19 3 4 wherein Y is chlorine or fluorine.

CHzOAc OHzOAc fin 'm T O WT 01110110 I HG CH 5 I ll HOf I EEO-p: ]F Y 7 s 11120111: OHzOAc 0:0 (1:0 '---0H I -o11 110 -F HO -F I 9 10 wherein Y is hydrogen, methyl, chlorine or fluorine.

n FLOW SHEET B 00 clmoAc 3112mm ]:0 (3:0

--o1-1 OH 1101 HO'/\: i i 40 O: 0:

CH2OII CHzOH 2:0 c =o OH OH 110 --Y H0 A --F .0 1

H2C\ HzC\ 1 011: L CH: --o -0 1101 1 r HOWA/ ]-F wherein Y is hydrogen, methyl, chlorine or fluorine.

TU Ti QJ gg zo wherein Y is hydrogen, methyl, chlorine or fluorine.

FLOW SHEET D nolAifiii rig rot wherein Y is chlorine or fluorine.

The following examples illustrate methods of carrying out the present invention but it is to be understood that these examples are given for purposes of illustration and not of limitation.

Example 1 To a. suspension of 25.0 g. of l6a-fluoro-1 lp,17a,21trihydroxy-4-pregnene-3,20-dione in 1.5 liters of alcoholtfree chloroform cooled to about 5 C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed twice With a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with methanol to afford a crystalline solid which is the 16::- fluoro 17u,20,20,21 b-is(methylenedioxy) 11B hydroxy-4-pregnene-3-one.

The 17a,2 0,20,21-bis(methylenedioxy)-l6afluoro-ll5- hydroxy-4-pregnene-3-one (1.350 g.) is dissolved in 23 ml. of dry, hot benzene and the resulting solution is cooled to room temperature and treated with 0.96 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred magnetically at room temperature over night. The mixture is poured into an excess of saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as the sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts are again aciditied With an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 17a,20,20,21-bis(methylenedioxy) -16OL-flllOTO-1 1,8- hydroxy-2-hydroxymethylene-4-pregnene-3-one.

The 17a,20,20,21-bis(methylenedioxy)-16a-fluor0-l lfihydroxy-2-hydroxymethylene-4-preguene-3-one (850 mg.) is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes then evaporated to dryness under reduced pressure. The residue is washed three times with cold Water and the resulting amorphous solid is dried at C. for 1 hour in high vacuum to give 17a,20,20,2l-bis(methylenedioxy)46afluoro-l 1 li-hydroxy-4-pregneno- 3 ,2-c] pyrazole.

The 17u,20,20,2l-bis(methylencdioxy)-16ot-fiuoro-11B- hydroxy-4-pregneno-[3,2-clpyrazole (720 mg.) is heated in a steam bath with 24 ml. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed under vacuum using a water bath at about 50 C. as the source of heat. The residue is flushed tour times with n-hexane and then dried at 60 C. in high vacuum to give a solid which is a mixture of IGa-fiUOI'O- 11,,17a,2l tnihydroxy 20 oxo 4 pregneno [3,2-c]- pyr-azole and l6ufiuoro-2l-formyloxy-l1B,17a-dihydroxy- 20-oxo-4-pregneno-[3,2-c]pyrazo1e, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 m1. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 16ofluO1'O-llfi,l7u,21- trihydroxy-ZO-oxo-4-pregnen0- [3 ,2-c] pyrazole.

To a solution of mg. of 16a-fluor0-11d,l7a,2l-trihydroxy-ZO-oxo-4-pregneno-[3,2-c]pyrazole in 2 ml. of pyridine is added two milliequivalents of acetic anhydride. The mixture is allowed to stand over night at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is Washed successively with water, ice-cold l N sulfunic acid (until the pH of the aqueous layer is 1-3), saturated 15 aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. under vacuum to afford the N-acetyl-16a-fluoro-115,1701, 2 l-trihydroxy-20 oxo-4-pregneno- [3 ,2-c] pyrazo le 21-acetate which is isolated by addition of water and filtration.

In accordance with the above procedure, but starting with the 16u-fluoro-11,8,170:,21-trihydroxy-20-oxo-4-pregneno-[3,2-c]pyrazole, and using two equivalents of another acylating agent there is obtained the corresponding N-acyl-Zl-acrylate thereof.

A solution of 5.73 g. of N-acetyl-16a-fluoro-1 l/3,17a,21- trihydroxy -20-oxo-4-pregneno-[3,2-c]pyrazole 21-acetate in 60 ml. of 80% (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is Washed with Water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness under vacuum. Recrystallization of the resulting product affords the 16a-fluoro-1lfl,17a,21-trihydroxy-20-oxo-4- pregneno- 3 ,2-c] pyrazole 21-acetate.

To a solution of 3.70 g. of 16a-fluoro-11,8,17u,21-trihydroxy-20-oxo-4-pregneno-[3,2-c]pyrazole 2l-acetate in 150 ml. of methanol there is added 30 ml. of water containing 0.01 mole of hydrogen chloride. Then a solution of 0.81 g. of potassium cyanate in 8 ml. of water is added and this mixture is left over night at room temperature. Some of the methanol is removed under vacuum on the rotating evaporator; more water is added and the precipitate is collected by filtration. Recrystallization from methanol gives the N-carbamyl pyrazole in sufficient purity for the next step.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.5 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed With n-hexane. The residue is washed with water, filtered and dried to constant weight to give N-carbamyl-16ecfluoro-l1fi,17a,21 trihydroxy-Z-oxo-4-pregneno-[3,2-c1- pyrazole.

To a solution of 85 mg. of N-carbamyl-16a-fluoro-11,8, 170:,21-trihydroxy-20-oxo-4-pregneno- [3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to 0 C. is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-carbamyl-16a-fluoro-11fi,17a,21-trihydroxy-20- oxo-.4-pre gneno.- [3,2-.c]pyrazole 21-mesylate.

To 180 mg. of N-carbamyl-16a-fluoro-llB,17a,21-trihydroxy-ZO-oxo-4-pregneno-[3,2-c]pyrazole 21-mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodine. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N.-carbamyl-16afluoro-1 13,17ot-dihydroxy-21-ido-20 oxo-4-pregneno-[3,2-c]pyrazole.

The N-carbamyl-16a-fluoro-115,17u-dihydroxy-21-iodo- .20-oxo-4-pregneno-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. T o the resulting suspension is added 500 mg. of sodium bisufite and the mixture is heated under reflux for period of about one hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-carbamyl- 16wfluoro 115,170 dihydroxy-2Q-oxo-4-pregneno-[3,2- cJpyrazole.

To a Solution 9f 62 gof :IN-carbamyl-16a-fluoro- 16 11,8,17a,21 trihydroxy 20-oxo-4-pregneno-[3,2-c]pyrazole ZI-mesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-carbamyl- 17a,21-epoxy 160a fluoro 1113 hydroxy-20-ox0-4-pregneno-[3,2-c]pyrazole and N-carbamyl-l6ix,2l-difluoro- 115,17a-dihydroxy-20-oxo 4 pregneno [3,2-c]pyrazole which compounds are separated by partition chromatography, or by chromatography on silica gel.

To a solution of 355 mg. of N-carbamyl-16a-fluorol 1B,17a-dihydroxy-ZO-oxo-4-pregneno-[3,2-c]pyrazole in 35 ml. of glacial acetic acid there is added slowly with stirring 104 mg. of sodium nitrate in 5 ml. of water. After fifteen minutes at room temperature, most of the acetic acid is removed at room temperature on the rotating evaporator. Ethyl acetate is added and this solution is extracted several times with sodium bicarbonate and then dried. Removal of the solvent, followed by chromatography on alumina affords 16a-fluoro-llfl,l7a-dihydroxy- 20-oxo-4-pregneno-[3,2-c]pyrazole.

In accordance with the above procedure, but starting with the N-carbamyl-l6a,2l-difluoro-11,6,17a-dihydroxy- 20-oxo-4-pregneno-[3,2-c]pyrazole there is obtained the 160:,21 difluoro l15,17a-dihydroxy-20-oxo-4-pregneno- [3,2-c]pyrazole.

Example 2 To a suspension of 25.0 g. of 6,16a-difluoro-11/i,17a,21- trihydroxy-4,6-pregnadiene-3,20-dione in 1.5 liters of alcohol-free chloroform cooled to about 5 C. in an ice bath is added with constant stirring 750 ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 7 hours. The layers are separated and the aqueous phase is backextracted twice with chloroform. The combined organic layers are washed twice with a 5% solution of sodium bicarbonate, and twice with a saturated salt solution. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is triturated with methanol to afford a crystalline solid which is the 6,160t-dlfillO1'O-17d,20,2lbl$ (methylenedioxy)-1l;8- hydroxy-4,6-pregnadiene-3-one.

The 17a,20,20,21 bis(methylenedioxy) 6,1601 difluoro-llfi hydroxy 4,6 pregnadiene 3 one (3.350 g.) is dissolved in 23 ml. of dry, hot benzene and the resulting solution is cooled to room temperature and treated with 0.96 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 560 mg. of sodium hydride (as a 58% dispersion in mineral oil) is added. The system is again evacuated and filled with nitrogen, and the mixture is stirred magnetically at room temperature over night. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as the sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether and into chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 1701,20, 20,21 bis(methylenedioxy) 6,16a difluoro hydroxy 2 hydroxymethylene 4,6 pregnadiene 3-one.

The 17a,20,20,21 bis(methylenedioxy) 6,16a difluoro 11,8 hydroxy 2 hydroxymethylene 4,6 pregnadiene-3-one (850 mg.) is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of

hydrazine hydrate dissolved in 0.16 ml. of absolute etha- 1101. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dry ess under reduced pressure. The residue is Washed three times with cold Water and the resulting amorphous solid is dried at 80 C. for 1 hour in high vacuum to give 17a, 20,20,21 bis(n ethylenedioxy) 6,150. dilluoro 11,8- hydroxyl,6-pregnadieno- 3 ,2-c1pyrazole.

The 170:,2Q,20,2l bis(inethylenedioxy) 6,1604 difluoro 11,8 hydroxy 4,6 pregnadieno [3,2-c]pyr azole (720 mg.) is heated in a steam bath with 24 ml. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed under vacuum using a Water bath at about 50 C. as the source of heat. The residue is flushed four times With n-hexane and then dried at 60 C. in high vacuum to give a solid which is a mixture of 6,16a-difluoro-11,8,170:,21-trihydroxy-20-oxo-4,6- pregnadieno [3,2-c1pyrazole and 6,16a diiiuoro 21- formyloxy 115,170: dihydroxy 20 oxo 4,6 pregnadieno-[3,2-c]pyrozole, which compounds are separated by chromatography.

A 500 mg. a iquot of this crude product is dissolved in ml. of are methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The allroxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-aexane. The residue is Washed with Water, filtered and dried to constant Weight to give 6,16adiiluoro ll/3,17a,21 trihydroxy 2O oxo 4,6 pregnadieno-[3,2-c1pyrozole.

To a solution of 100 mg. of 6,l6c-.-diiluoro-1113,111,21- trihydroxy 20 oxo 4,6 pregnadieno[3,2-clpyrazole in 2 m1. of pyridine is added tWo milliequivalents of acetic anhydride. The mixture is allowed to stand over night at room temperature. A mixture of ice and Water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is \v shed successively with Water, ice-cold l N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (unti the pH of the aqueous layer is 8), and Water (until tli aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. under vacuum to afford the N-acetyl 6,16a diiluoro llfi,l7u,2l trihydroxy 20- oxo 4,6 pregnadieno [3,2-c]pyrazole Ell-acetate Which is isolated by addition of Water and filtratiton.

in accordance with the above procedure, but starting with th 6,16a-difiuoro-11B,170,2l-trihydroxy-20-oxo- 4,6-pregnadieno-[3,2--c]pyrazole, and using two equivalents of another acylating agent there is obtained the corresponding N-acyl-Zl-acylate thereof.

A solution of 5.73 g. of N-acetyl-6,la-difiuoro-l1B, 1704,21 trihydroxy 20 oxo 4,6 pregnadieno-[3,2-c]- pyrazole 2l-acetate in 60 ml. of 80% (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-Water and extracted with ethyl acetate. The ethyl acetate extract is Washed with Water with saturated sodium bicarbonate solution, dried, and evaporated to dryness under vacuum. Recrystallization of the resulting product affords the 6,l6 x-difluoro17a,21-dihy droxy 11,20 dioxo 4,6 pregnac ieno [3,2-c1pyrazole ZI-acetate.

To a solution of 3.70 g. of 6,l6a-diiiuoro-11fi,17a, 21- trihydroxy 20 oxo 4,6- pregnadieno [3,2-c1pyrazole 21-acetate in 150 ml. of methanol there is added 30 ml. of water containing 0.01 mole of hydrogen chloride. Then a solution of 0.81 g. of potassium cyanate in 8 ml. of Water is added and this mixture is left over night at room temperature. Some of the methanol is removed under vacuum on the rotating evaporator; more Water is added and the precipitate is collected by filtration. Recrystallization from methanol gives the N-carbarnyl-pyrazole in sufiicient purity for the next step.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The allroxide is neutralized with acetic acid and the mixture is then taken to dryness and fiushed with n-hexane. The residue is Washed with Water, filtered and dried to constant Weight to give N-carbamyl-dlGu-difiuoro llfi,l7oz,2l trihydroxy 20 oxo 4,6 pregnadieno-[3,2-c]pyrazole.

To a solution of mg. o2 N-carbamyl-G,lda-difiuoroll,B,l7o.,2l trihydroxy 20 oxo 4,6 pregnadieno- [3,2-c1pyrazo-le in 0.5 ml. of pyridine, cooled to 0 C. is added 0.015 ml. of methane sultonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, Washed with Water, and dried to give N-carbamyl-6,16a-diiluoro- 1l[3,17ot,2l trihydroxy 20 xo 4,6 pregnadieno- [3,2c1pyra-zole 21-mesylate.

To 180 mg. of N-carbamyl-6,l6a-difluoro-l1 63170431- trihydroxy 20 oxo 4,6 pregnadicno [3,2 c]pyrazoie Zlunesylate dissolved in 10 ml. oi acetone is added 300 of sodium iodide. The resulting mixture is heated at reflux temperature for a period or" approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which pr cipl ates is recovered by filtration, Washed with Water, and dried to give N-oarbamyl-6,l6a-difiuoro-llp3,l7a-dihydroxy 2 1 iodo 20 oxo 4,6 pregnadieno [3,2- 0] pyrazole.

The N-carbamyl-6,16a-difiuoro- 1B,17c-dihydroxy-21- iodo 20 oxo 4,6 pregnadieno [3,2-c]pyr.azole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 50 0 mg. of sodium bisulfite and the mixture is heated under reflux for a period of about one hour. The reaction solution is cooled, diluted With water, and the material which separates is recovered by filtration. The product is washed With water, dried and recrystallized from ethyl acetate to give N-carbarnyl 6,16a difiuoro 116,170: dihydroxy 20 oxo- 4,6-pregnadien-o-[3,2-c1pyrazole.

To a solution of 62 mg. of N-carbamyl-6,16a-difluoro- 11,3,17c4,2.tl trihydroxy 20 oxo 4,6 pregnadieno- [3,2-c1pyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimeth'y-liormamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-carbamyl 17a,21 epoxy 6,16a diiluorohydroxy 20 oxo 4,6 pregnadieno [3,2 cJpyrazole and N-carba1nyl-6,-'16a,2l-triiluoro-llfi,17a-dihydroxy 20 oxo 4,6 pregnadieno [3,2 c]pyrazole which compounds are separated by partition chromatography, or by chromatography on silioal gel.

To a solution of 355 mg. of N-carbamyl-6,16a-difluoro- 115,176; dihydroxy 20 oxo 4,6 pregnadieno [3,2- clpyrazole in 35 ml. of glacial acetic acid there is added slowly with stirring 104 mg. of sodium nitrite in 5 of Water. After fifteen minutes at room temperature, most of the acetic acid is removed at room temperature on the rotating evaporator. Ethyl acetate is added and this solution is extracted several times with sodium bi carbonate and then dried. Removal of the solvent, followed by chromatography on alumina afford 6,160L-dlllluoro llfi,17o: dihydroxy 20 oxo 4,6 pregnadieno- [3,2-c1pyrazole.

in accordance with the above procedure, but starting with the N-caroamyl-6,16a,21-trifiuoro-l.1/3,17a-dihydroxy 29 oxo 4,6 pregnadieno [3,2 c]pyrazole there is obtained the 6,l6a,21-trifluoro-1l{3,17a-dihydroxy- 20-oxo-4,6-pregnadieno [3,2-c1pyrazole.

19 In accordance with the above procedures, but starting with the 16a-fiuoro-1 113,170:,21-trihydroxy-6-rneth-yl-4,6- pregnadiene-3,ZO-dione in place of the 6,16oc-difiufO-11B, 170.,21-trihydroxy-4,6-pregnadiene-3,20-dione, there are obtained as products the corresponding 16a-fluoro-11B, l7c,2l trihydroxy 6 methyl 20 oxo 4,6 pregnadieno-[3,2c]pyrazole and the N-acyl-, the 21-acylate, and the- N-acyl 21-acylate derivatives thereof; the 1604- fiuoro 115,17 dihydroxy 6 methyl 20 oxo 4,6- pregnadieno-[3,2-c1pyrazole and the N-acyl derivatives thereof; and the '16a,21-difiuoro-11,6,17a-dihydroxy-6- methyl-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole and the N-acyl derivatives thereof.

Example 3 To a suspension of 10 g. of 9a,1 1fl-diCl1lOI0-16a-fiu010- 17a,21-dihydroxy-4-pregnene-3,20-dione in 475 ml. of alcohol-free chloroform and 300 ml. of methylene chloride, cooled to about C. in an ice bath, is added with constant stirring 189 m1. of cold, concentrated hydrochloric acid and then 189 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 2 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed with water, then with a 5% solution of sodium bicarbonate and again with water. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is flushed three times with methanol. Hot methanol is then added and the product is filtered and then crystallized from a mixture of methylene chloride and n-hexane to give 17a,20,20,21-bis(methylenedioxy)- 9a,11[3-dichloro-l6or-fiuoro-4-pregnene-3-0ne.

The 17a,20,20,21 bis(methylenedioxy) 9a,1l/3 dichloro-16a-fluo-ro-4-pregnene-3-'one (500 mg.) is suspended in 8.5 cc. of dry benzene and treated with 0.15 ml. of freshly distilled ethyl fonnate. The air in the system is replaced with nitrogen and 225 mg. of sodium hydride (as a 58% dispersion in mineral oil is added). The system is again evacuated and filled with nitrogen. The mixture is stirred under nitrogen for /2 hour after which time 0.2 ml. of ethyl formate is added and the mixture is stirred magnetically at room temperature over night. The mixture is poured into an excess of a saturated aqueous solution of sodium dihydrogen phosphate and the product is extnacted four times with benzene. The organic extracts are washed three times with Water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as a sodium salt by extraction into a solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 17a,20,20,21-bis- (methylenedioxy) 90,11/3 dichloro 16a fluoro 2- hydroxymethylene-4-pregnene-3-one.

The 170c,20,2Q,2l-b1$ (methylenedioxy)-9oz,1 l fi-dichloro- 16a fluoro 2 hydroxymethylene-4-pregnene-3-one (65 mg.) is dissolved in 0.7 ml. of absolute ethanol and treated with a solution of 0.12 ml. of hydrazine hydrate dissolved in 0.12 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is dissolved in chloroform and petroleum ether is added to give a solid which is 17u,20,2021-bis(methylenedioxy) 9a,11,8 dichloro 16a fiuoro-4-pregneno-[3, 2-c]pyrazole.

The 17a,2 0,20,21-bis(methylenedioxy) 9a,11,8-dichloro-16a-tluoro-4-pregneno-[3,2-c1pyrazole (25 mg.) is heated on a steam bath with 5 cc. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed under reduced pressure using a water bath at about 50 C. as the source of heat. The residue is flushed with n-hexane. Th residue is then dissolved in acetone and precipitated with n-hexane to give an amorphous solid which is a mixture of 90,llB-di0l1lOfO-l6ocfluoro l7oc,2l dihydroxy-20-oxo-4-pregneno-[3,2-c]pyrazole and 9 x,l1fi,-dichloro-16o-fluoro-21-formyloxy-17o:- hydroxy-20- xo-4-pregneno-[3,2-c]pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered and dried to constant weight to give 90,11 fl-dichloro-l6a-fluoro 17a,21-dihydroxy-20-oxo-4-pregneno-[3,2-c]pyrazole.

To a solution of 100 mg. of 904,11B-diChl0r0-16oz-lu0r0- 17a,2l dihydroxy 20 oxo 4 pregneno-[3,2-c]pyrazoie in 2 ml. of pyridine is added two milliequivalents of acetic anhydride. The mixture is allowed to stand over night at room temperature. A mixture of ice and water is then added. After standing for about minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with Water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 13), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and Water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about C., under vacuum. The product is then crystallized from a solvent; alternately, the product may be chromatographed on alumina to give the N-acetyl9e,11,8- dichloro 16c: fluoro 17a,21-dihydroxy-20-oxo-4-pregneno-[3,2-c]pyrazole 21-acetate, which is isolated by crystallization of the appropriate eluate.

In accordance With the above procedures, but starting with the 9a,11,B-dichloro-16a-fiuoro-17a,21-dihydroxy-20- oxo-4-pregneno-[3,2-c1pyrazole and using two equivalents of another acylating agent there is obtained the corresponding l -acyl-2l-acylate thereof.

A solution of 5.73 g. of N-acetyl-9a,11,8-dichloro-16afiuoro 17a,21-dihydroxy 20 oxo 4-pregneno-[3,2-c]- pyrazole 21-acetate in ml. of (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is Washed with Water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness under vacuum. Recrystallization of the resulting product affords 904,11,B-CliChlOrO16ec-flU010-17a, 21-dihydroxy-20=oxo-4-pregneno-[3,2 c]pyrazole 21-acetatc.

To a solution of 3.70 g. of 9a,11/3-dichloro-16a-fiuoro- 17:1,2 1-dihydroxy-20-oxo-4-pregneno- [3,2-c1pyrazole 21- acetate in 150 ml. of methanol there is added 30 ml. of Water containing 0.01 mole of hydrogen chloride. Then a solution of 0.81 g. of potassium cyanate in 8 ml. of water is added and this mixture is left over night at room temperature. Some of the methanol is removed under vacuum on the rotating evaporator; more water is added and the precipitate is collected by filtration. Recrystallization from methanol gives the N-carbamyl pyrazole in sufiicient purity for the next step.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere: for ten minutes. The alkoxide is neutralized with acetic: acid and the mixture is then taken to dryness and flushed. with n-hexane. The residue is washed with Water, filtered and dried to constant weight to give N-carbamyl-9a,11/3- dichloro 16a fiuoro 17u,21-dihydroxy-20-oxo-4-preg-- To a solution of mg. of N-carbamyl-9a,llfl-dichloro- 16a fiuoro 17a,21 dihydroxy 20 oxo-4-pregneno-[3, 2-c]pyrazoie in 0.5 ml. of pyridine, cooled to 0 C., is added 0.015 ml. of methane sulfonylchloride. The resulting mixture is allowed to stand at; a. temperature of sli es? 21 approximately C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, washed with water, and dried to give N-carbamyl-9a,l1B-dichloro-16eiluoro 171:,21 dihydroxy 20 oxo-4-pregneno-[3,2-c]- pyrazole 21-mesylate.

To 180 of N-carbamyl-Sa,llfl-dichloro-lda-fiuoro- 17 .,21-dihydroxy-20-oxo-4-pregneno- 3,2-c] pyrazole 2 1- mesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a p riod of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with Water. The material which precipitates is recovered by filtration, washed with Water, and dried to give N-carbamyl-9u,llfl-dichloro-l6a-fluoro-l7e-hydroxy2 1-iodo-20-oxo-4-pregneno- [3,2-c] pyrazole.

The N carbamyl 902,1ldlCl1lOIO-16a-fiL1OIO-i7ca-l'lY- droxy-2l-iodo-ZO-oxol-pregneno-[3,2-c1pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, dilluted with water, and the material which separates is recovered by filtration. The product is washed with Water, dried and recrystallized from ethyl acetate to give N-carbamyl-9a,l1B-dichloro-16a-fiuoro- 17a-hydroxy-20-oxo-4-pregneno- [3,2-c] pyrazole.

To a solution of 62 mg. of N-carbamyl-9u,l lfi-dichloro- 16e-iluoro-l7e,21-dihydroxy-20-oxo-4-pregneno-[3,2 c]- pyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dimethyliormamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is then added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-oarbamyl-9a,11fl-dichloro-16m-luoro-l7a,2lepoxy-ZO-oxol-pregneno-[3,2-c]pyrazole and N c-arbanljl-S'uc,1lfl-diClllOrOdficqZl-CliflLlOlO 17a hydroxy-ZO- oxol-pregneno[3,2-c]pyrazole, which compounds are separated by partition chromatography or by chromotography on silica gel.

To a solution of 355 mg. of N-caroamyl-9a,1lB-dichloro-l6a-liuoro-17e-hydroxy-20-oxo-4-pregueno [3,2- c]pyrazole in 35 ml. of glacial acetic acid there is added slowly with stirring 104 of sodium nitrite in 5 ml. of water. After fifteen minutes at room temperature, most of the acetic acid is removed at room temperature on the rotating evaporator. Ethyl acetate is added and this solution is extracted several times with sodium bicarbonate and then dried. Removal of the solvent, followed by chrornatography on alumina, affords 906,11fidichloro-16a-fiuoro-17a-liydroxy-20-oxo-4-pregneno 3,2- clpyrazole.

in accordance with the above procedures, but starting with the N carbamyl-9ct,1lo-dichloro-l6a,21-difluoro- 17a-hydroxy2 )-oxo4-pregneno-[3,2-c1pyrazole there is obtained the corresponding 9cc,1l-dlChlOIC-16a,Z1-Cllfiuorol 7e-hydrQXy-ZG-oxO- ipmgneno- 3,2-c] pyrazole.

Example 4 To a suspension of 10 g. of 90:,11B-diCl1lOrD-l6a-fiu0fo- 17,2l-dihydroxy-6-methyl-4,6pregnadiene-3,20-dione in 475 ml. of alcohol-free chloroform and 300 ml. of methylene chloride, cooled to about 5 C. in an ice bath, is added with constant stirring 189 ml. of cold, concentrated hydrochloric acid and then 189 ml. of formalin (low in methanol). The mixture is removed from the ice bath and stirred at room temperature for 2 hours. The layers are separated and the aqueous phase is back-extracted twice with chloroform. The combined organic layers are washed with water, then with a 5% solution of sodium bicarbonate and again with water. The solution is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is flushed three times with methanol. Hot methanol is then added and the product is filtered and then crystallized from a mixture of methylene chloride and n-hexane to give 17a,20,20,21-bis- (methylenedioxy)-9ot,1lfi-dichloro-lda-fluoro-6 methyl- 4,6-pregnadiene-3-one.

The Hot/20,202 l-bis (methylenedioxy) 91x,1 1 [i-dichloro- 16uluoro-6-methyl-4,6-pregnadiene-3-one(500 mg.) is suspended in 8.5 cc. of dry benzene and treated with 0.15 ml. of freshly distilled ethyl formate. The air in the system is replaced with nitrogen and 225 mg. of sodium hydride (as a 58% dispersion in mineral oil is added). The system is again evacuated and filled with nitrogen. The mixture is stirred under nitrogen for /2 hour after which time 0.2 ml. of ethyl formate is added and the mixture is stirred magnetically at room temperature over night. The mixture is poured into an excess or" a saturated aqueous solution of sodium dihydrogen phosphate and the product is extracted four times with benzene. The organic extracts are washed three times with water and dried over sodium sulfate. Removal of the solvent gives the crude product which is dissolved in ether and purified as a sodium salt by extraction into a 10% solution of sodium carbonate. The aqueous alkaline extracts are again acidified with an excess of a saturated aqueous solution of sodium dihydrogen phosphate and extracted into ether. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 17u,20,20,21 bis(methylenedioxy)-9a,11B-dichloro-16efiuoro 2 hydroxymethylene-d nethyl-4,6-pregnadiene- 3-one.

The 17a,20,20,2 l-bis (methylenedioxy) -9 a, 1 1 Bdichloro- 16u-fluoro-2hydroxymethylene-6-methyl-4,G- regnadiene- 3-one (65 mg.) is dissolved in 0.7 ml. of absolute ethanol and treated with a solution of 0.12 ml. of hydrazine hydrate dissolved in 0.12 ml. of absolute ethanol. The mixture is refluxed in a nitrogen atmosphere for about 45 minutes and then evaporated to dryness under reduced pressure. The residue is dissolved in chloroform and petroleum ether is added to give a solid which is 17; 20,20,21 bis (methylenedioxy)-9a,11fldiehloro-16afiuoro- 1 6-methyl-4,-pregnadieno- [3 ,2-c] pyrazole.

The 17a,20,20,21 bis(methylenedioxy) 9 x,l1,8 dichloro 16a fluoro 6 methyl 4,6 pregnadieno- [3,2-clpyrazole (25 mg.) is heated on a steam bath with 5 cc. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed under reduced pressure using a Water bath at about 50 C. as the source of heat. The residue is flushed with n-hexane. The residue is then dissolved in acetone and precipitated with n-hexane to give an amorphous solid which is a mixture of 9e,11B-dichloro-16a-fluoro-17e,2l-dihydroxy- 6 methyl 20 oxo 4,6 pregnadieno [3,2-c1pyrazole, and ,1lfi dichloro 16a fiuoro 21 formyloxy- 17a hydroxy 6 methyl 20 oxo 4,6 pregnadieno- [3,2-c1pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The aliroxide is neutralized. with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with water, filtered, and dried to constant Weight to give 9w,11o-dichl0- ro 16cc fiuoro 1704,21 dihydroxy 6 methyl 20- oxo-4,6-pregnadieno-[3,2-c]pyrazole.

To a solution or" mg. of 9a,11[3-dich1oro-16afluoro 170.,21 dihydroxy 6 methyl 20 oxo 4,6- pregnadieno-[3,2-c1pyrazole in 2 ml. of pyridine is added two tmilliequivalents of acetic anhydride. The mixture is allowed to stand over night at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 13), saturated aqueous sodium bi-- carbonate (until the pH of the aqueous layer is 8), and. water (until the aqueous layer is neutral). The ethyl acetate solution is dried With anhydrous sodium sulfate. The solvent is then distilled at about 40 C., under vacu- 11m. The product is then crystallized from a solvent; al-- ternately, the product may be chromatographed on alu-- mina to give the N-21Ce y1-9Dg].lfi-diChIOIO-IGOt-flHOI'O" l7a,21 dihydroxy 6 methyl 20 oxo 4,6 pregna-- dieno-[3,2-c]pyrazole 21-aoetate, which is isolated by crystallization of the appropriate eluate.

In accordance with the above procedures, but starting with the 906,1lfl-diChIOI'O-160t-fiuOI'O-1706,21-dlhYdfOXY-6- methyl-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole and using two equivalents of another acylating agent there is obtained the corresponding N-acyl-21-acylate thereof.

A solution of 5.73 g. of N-acetyl-9ot,11,6-dichloro-16afiuoro 1711,21 dihydroxy 6 methyl 20 oxo 4,6- pregnadieno-[3,2 c]pyrazoie 21-acetate in 60 ml. of 80% (v./v.) acetic acid is refluxed for 1.5 home. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is washed with Water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness under vacuum. Recrystallization of the resulting product affords 911,115- dichloro 16cc fluoro 17a,21 dihydroxy 6 methyl- 20-oxo-4,6-pregnadieno-[3,2-c1pyrazole 21-acetate.

To a solution of 3.70 g. of 9a,11,8-dichloro-16ot-fluoro- 1704,21 dihydroxy 20 oxo 4,6 pregnadieno [3,2- cJ-pyrazole 2l-acetate in 150 ml. of methanol there is added 30 ml. of water containing 0.01 mole of hydrogen chloride. Then a solution of 0.81 g. of potassium cyanate in 8 ml. of water is added and this mixture is left over night at room temperature. Some of the methanol is removed under vacuum on the rotating evaporator; more water is added and the precipitate is collected by filtration. Recrystallization from methanol gives the N-carbarnyl-pyrazole in sufiicient purity for the next step.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.5 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is Washed with water, filtered and dried to constant Weight to give 1 -carbamyl-9a,11p-dichloro 16a fluoro 17a,21 dihydroxy 20 oxo 4,6- pregnadieno- [3,2-c] pyrazole.

To a solution of 85 mg. of N-carbainyl-9ot,11/3-di chloro 16a fiuoro -17a,21 dihydroxy 6 methyl 20- oxo-4,6-pregnadieno-[3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to C., in added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the precipitate which forms is recovered by filtration, Washed with water, and dried to give N-carbamyl 900,113 dichloro 16cc fluoro 17a,2l dihydroxy 6 methyl 20 oxo 4,6 pregnadieno [3,2-c]- pyrazole 21-mesylate.

To 180 mg. of N carbamyl 9u,llfl-dichloro-l6afluoro 17u,21 dihydroxy 6 methyl 20 oxo 4,6- pregnadieno-[3,2 c]pyrazole 21-mesylate dissolved in ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, washed with water, and dried to give N-carbamyl 911,115 dichloro 160a fiuoro 17cc hydroxy- 6 methyl 21 iodo oxo 4,6 pregnadieno- .[3,2-c] pyrazole.

' of sodium nitrite in 5 ml. of water.

The N carbamyl ,1lit-dichloro-16ot-fiuoro-17ct-hydroxy 21 iodo 6 methyl 2O oxo 4,6 pregnadieno-[3,2-c1pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted water, and the material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give N-carbamyl-9a,1lfi-dichloro- 160a fluoro 17oz hydroxy 6 methyl 20 oxo 4,6- pregnadieno- 3,2-c1pyrazole.

To a solution of 62 mg. of Ncarbamyl-9a,1Iii-dichloro- 16a fluoro 1704,21 dihydroxy 6 methyl 20 oxo- 4,6 pregnadieno [3,2 cJpyrazole 21 mesylate in '1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at C. for 20 hours. Water is then added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of N-carbamyl-9a,llfi-dichloro l7a,21 epoxy 16a fluoro 6 methyl 20- oxo 4,6 pregnadieno [3,2 c]pyrazole and N carbamyl 9a,1l[3 dichloro 16:,21 difluoro 170a hydroxy 6 methyl 20 oxo 4,6 pregnadieno [3,2-c]

v pyrazole, which compounds are separated by partition chromatography or by chromatography on silica gel.

To a solution of 355 mg. of N-carbamyl-9a,11fi-dichloro 16a fiuoro 17a hydroxy 6 methyl 20- -oxo-4,6-pregnadieno-[3,2-c]pyrazole in 35 ml. of glacial acetic acid there is added slowly with stirring 104 mg.

After fifteen minutes at room temperature, most of the acetic acid is removed at room temperature on the rotating evaporator. Ethyl acetate is added and this solution is extracted several times with sodium bicarbonate and then dried. Removal of the solvent, followed by chromatography on alumina affords 90;,11;3-dichloro-16a-fiuoro17a-hydroxy-6- methyl-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole.

In accordance with the above procedure, but starting with the 1 -carbamyl-9a,11,8-dichloro-l6a,2l-difiuoro-l7uhydroxy 6 methyl 20 -oxo 4,6 pregnadieno [3,2-c] pyrazole there is obtained 9a.,l1,8-dichloro-16a,21-difluoro 171x hydroxy 6 methyl 20 oxo 4,6 pregnadieno-[3,2-c]pyrazole.

In accordance with all of the above procedures, but starting with the 90,1lfi-dichloro-6,l6a-diiluoro-17a,2l-dihydroxy 4,6 pregnadiene 3,20 dione in place of the 911,115 dichloro 16o: fiuoro 17CL,21 dihydroxy- 6-rnethyl-4,6-pregnadiene-3,ZO-dione there are obtained as products the corresponding 901,1lfi-dichloro-dlM-difluoro 17o,21 dihydroxy 2O oxo 4,6 pregnadieno- [3,2-c]pyrazole and the N-acyl-, the 2l-acylate, and the N-acyl-Zl-acylate derivatives thereof in which the two acyl groups may be the same or dilferent; the 9a,llfldichloro 6,16a difiuoro 17a hydroxy 20 oxo 4,6- pregnadieno[3,2-c1pyrazole and the N-acyl derivative thereof; and the 9ct,1lfl-dichloro-,l6a,2l-trifluoro-l7ahydroxy-20-oxo-4,6-pregnadieno- 3,2-c] pyrazole and the N-acyl derivatives thereof.

Example 5 A 5 g. sample of 9oal6a-difluoro-1lB,l7ot,2l-trihydroxy-4,6-pregnadiene-3,ZO-dione is dissolved in a mixture of 235 ml. of chloroform and ml. of methylene chloride, cooled in an ice bath with stirring and treated with 85 ml. of formaldehyde (27%). An equal volume (85 ml.) of cold concentrated hydrochloric acid is added from a funnel over a 5-minute interval with stirring and cooling. The mixture is stirred at room temperature for four hours. The layers are separated and the organic layer is washed free of acid by washing three times with Water and then with a 5% solution of sodium bicarbonate. The organic layers are washed free or" bicarbonate, dried over magnesium sulfate and taken to dryness. The gummy residue is treated with enough hot methanol on a steam bath to eifcct trituration, and the resulting crystalline solid is separated by filtering the mixture while hot. (The filtrate is set aside and may deposit additional product over night.) The crude product is dried to constant Weight and purified by chromatography. The product is partially dissolved in 250 ml. of hot chloroform and diluted with an equal volume of hot benzene to complete solution. After cooling, the mixture is adsorbed in 100 g. of basic alumina and eluted with benzene and chloroform to give 17,20,20,21-bis (methylenedioxy) 9a,16e difiuoro 11,8 hydroxy- 4,6-pregnadiene-3-one.

The l7cz,20,20,21 bis(methylenedioxy) 9a.,l6rx difluoro-ll,B-hydroxy-4,6-pregnadiene-S-one (3.25 g.) is dissolved in 76 ml. of dry pyridine and added to a cold solution prepared by the cautious addition of 3.25 g. of chromium trioxide (in portions) to 34.7 ml. of cold pyridine. The mixture is allowed to stand at room temperature over night. The mixture is poured into water and extracted three times with ethyl acetate, avoiding excessive shaking especially during the third extraction. The combined ethyl acetate extracts are washed three times with 1 N sulfuric acid and then with water until neutral. The combined ethyl acetate extracts are dried over magnesium sulfate and taken to dryness to give 2.94 g. of product. The product is dissolved in benzene, adsorbed on basic alumina and eluted with 8.2 benzene:chloroform to give 17a,20,20,2l-bi$ (methylenedioxy)9-a,16edi more-4,6-pregnadiene-3,1l-dione.

A 2.60 g. sample of l7a,20,20,21-bis(methylenedioxy) 91,161 -difluoro 4,6 pregnadiene 3,11 dione is dissolved in 95 ml. of dry benzene using dry equipment and treated with 2.43 ml. of freshly distilled ethyl formate. About 1.19 g. of a dispersion of sodium hydride in mineral oil (about 51%) is added, followed by about 1.19 g. of freshly prepared dry sodium methoxide (dried at about 175 C. using an oil pump for 4 hours). The air in the system is again replaced with nitrogen and the mixture, which turns yellow at once, is stirred at room temperature for one and one half hours. At this point the color of the reaction mixture is a dark orange. The mixture is chilled in an ice bath and a cold, saturated solution of sodium dihydrogen phosphate is added gradually to decompose excess sodium hydride and neutralize the sodium methoxide. Ether is added and the layers are separated. The aqueous layers are back-extracted with ether and the combined organic layers are Washed free of acid with water and then extracted three to four times with a 5% aqueous solution of sodium bicarbonate. These extracts are set aside. The product is now extracted four to five times with a cold 2% aqueous solution of sodium hydroxide. (in order to avoid emulsification, the aqueous alkali is gently poured into the separatory funnel and the layers are separated without shale ing the funnel. The last two extracts may be shaken with care.) The dark liquor is back-extracted two times with etl er, and finally acidified in the cold with saturated aqueous solution of sodium dihydrogen phosphate. The neutral ether-benzene fraction should be set aside and processed as described below. The product is extracted into ether, and the ether extracts are washed free of acid with a saturated solution of sodium chloride. After drying over magnesium sulfate, the ether solution is taken to dryness and the amorphous product is crystallized from methanol to give 17a,20,20,21-bis(methylenedioxy)- 90,160 diiiuoro 2 hydroxymethylene 4,6 pregnadiene-3,11-dione. This material is satisfactory for use in the next step.

A 1.00 g. aliquot of 17e,20,20,21-bis(methylenedioxy) 9a,16a. difiuoro 2 hydroxymethylene 4,6 pregnadiene-3,11-dione is suspended in 44 ml. of absolute ethanol and treated with 0.38 ml. of hydrazine hydrate (99- 100%). The air in the system is replaced with nitrogen and the mixture is quickly brought to the reflux temperature. After refluxing for one hour the mixture is taken to dryness; the residual oil is treated With water and the resulting amorphous solid is removed by filtration, washed thoroughly with water and dried. The yield is about 900 mg. The crude product is dissolved in absolute ethanol and concentrated under vacuum until the solid separates. The solid is redissolved by heating, and then allowed to crystallize slowly to altord 17a,20,20,21-bis(methylene dioxy) 91x iluoro 16a methyl 11 oxo 4,6 pregnadieno-[3,2-c]pyrazole.

A 455 mg. aliquot of 17a,20,20,21-bis(rnethylenedi oxy) 9 x,16a difluoro 11 oxo 4,6 pregnadieno- [3,2-c]pyrazole is suspended in 75 ml. of a solution of sodium borohydride in isopropanol which is prepared by suspending an excess of sodium borohydride in isopropa nol, stirring vigorously for about 15 minutes, and filtering to separate the excess of sodium borohydride. To the suspension is added an 0.816 ml. aliquot of a solution of 0.55 ml. of triethylamine in 1.45 ml. of isopropanot. The mixture is stirred, and enough methylene chloride (about 30 ml.) is added, with cooling, to make the system homogeneous. One drop of Water (ca. 1/20 ml.) is added and the mixture is stirred in a nitrogen atmosphere at room temperature over night. lnsolubles generally separate out in the course of the reaction. The mixture is then cooled, and the excess of sodium borohydride is decomposed by the addition of cold 2.5 N hydrochloric acid. The mixture (pl-l ca. 5) is taken to dryness under vacuum and the residue is Washed with water and dried to give 17a,20,20,2l-bis(rnethylenedioxy) 96,16U. diiluoro 11,8 hydroxy 4,6 pregnadieno- 3 ,Z-e] pyrazole.

The 17a,20,20,21-bis(methylenedioxy)-9a,16 x-diiiuoro- 11,8 hydroxy 4,6 pregnadieno [3,2 c]pyrazole (25 mg.) is heated on a steam bath with 5 cc. of a 60% aqueous solution of formic acid for about 30 minutes. The excess reagent is removed under reduced pressure using a water bath at about 56 C. as the source of heat. The residue is flushed with n-hexane. The residue is then dissolved in acetone and precipitated with n-hexane to give an amorphous solid which is a mixture of ,16cc-difll1010- 11[3,l7a,21 trihydroxy- 2O oxo 4,6 -pregnadieno- [3,2-c1pyrazole and 9e,16a-dilluoi'o-21forrnyloxy-11B, 17c: dihydroxy 2O oxo 4,6 pregnadieno [3,2-c] pyrazole, which compounds are separated by chromatography.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for ten minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed with Water, filtered and dried to constant weight to give 9a,16a diiluoro 115,170.,21 trihydroxy 20 oxo 4,6 pregnadieno-[3,2-c1pyrazole.

To a solution of mg. of 9e,16u.-dirluoro-l1@,17e,21- trihydroxy-20-oxo-4,6-pregnadieno-[3,2-c1pyrazole in 2 ml. of pyridine is added two milliequivalents of acetic anhydride. The mixtures is allowed to stand over night at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is Washed successively with Water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 3), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. under vacuum. The N-acetyl-9e,1dot-diiluoro-l13,17, 21-trihydroxy 20 oxo 4,6 pregnadieno [3,2 c] pyrazole 21-acetate is then isolated by addition of water and filtration.

In accordance with the above procedure, but starting 2? with the 9a,l6c4-diiluoro 11/3,l7c ,2l trihydroxy 20- oxo-4,6-pregnadieno-[3,2-c1pyrazole and using two milliequivalents or" another acylating agent, there is obtained the corresponding N-acyl-Zl-acylate thereof.

A solution of 5.73 g. of N&Cyi-9cc,16o:-(llflUOfO-11B, l7cc,2l-trihydroxy 20 oxo 4,6-pregnadieno-[3,2-c]- pyrazole 2l-acetate in 60 ml. of 80% (v./v.) acetic acid is refluxed for 1.5 hours. This solution is diluted with 400 ml. of ice-water and extracted with ethyl acetate. The ethyl acetate extract is Washed with water and with saturated sodium bicarbonate solution, dried, and evaporated to dryness under vacuum. Recrystallization of the resulting products affords 9d,l6zz(llflllOfO-l1fi,17m,2l-tli hydroxy 20 oxo-4,6-pregnadieno-[3,2-c1pyrazole 21- acetate.

To a solution of 3.70 g. or" 90,16oc-(liflUOfO-l15,170c,2 ltri'hydroxy 20 oxo-4,6-pregnadieno-[3,2-c]pyrazole 21-acetatc in 150 ml. of methanol there is added 30 ml. of water containing 0.01 mole of hydrogen chloride. Then a solution of 0.8l of potassium cyanate in 8 ml. of water is added and this mixture is left over night at room temperature. Some of the methanol is removed under vacuum on the rotating evaporator; more Water is added and the precipitate is collected by filtration. Recrystallization from methanol gives the N-car-bemylpyrazole in sufficient purity for next step.

A 500 mg. aliquot of the above compound is dissolved in 2.4 ml. of pure methanol and allowed to react With 0.5 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under nitrogen atmosphere for ten. minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is Washed with Water, filtered and dried to constant weight to give N-carbamyl- 9a,l6u-difluoro 1lfi3,17c:,21 trihydroxy 20 oxo-4,6-

pregnadieno-[3,2-c1pyrazole.

To a solution of 85 mg. of N-carbamyl-9a,lfia-difluoro- 11fi,17a,21-trihydroxy 20 oxo 4,6 pi'egnadieno-[3,2- cjpyrazole 2l-acetate in '05 ml. of pyridine, cooled to o C., is added 0.015 ml. of methane sulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately C. for a period of approximately 1 hour. Water is the added to the reaction mixture and the precipitate which forms is re covered by filtration, washed with Water, and dried to give N-carba:myl-9a,l6u-difluoro-ll,8,l7a,21-trihydroxy 20- oxo-4,6-pregnadieno- 3,2-c1pyrazole 2 l-mesylate.

To 180 mg. of N-carbamyl-9rt,lda-diiluoro 115,17, 21-trihydroxy 20 oxo 4,6-pre gnadi no-[3,2-c]pyrazole 2l-mesylate dissolved in ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately one hour, and the reaction solution is cooled to room temperature and diluted with water. The material which precipitates is recovered by filtration, Washed with water,

- and dried to give N-carbarnyl-9oi,lowdifiuoro-l15,17-

dihydroxy-Zl-iodo oxo-4,6pregnadieno-[3,2c]pyrazole.

The N-carbamyl-9 0:, l dct-difi-uorod 1,6, 17: -dihydroxy-2 l iodo-20-oxo-4,G-pregnadieno[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 50 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hr. The reaction solution is cooled, dilute-d with water, the material which separates is recovered by filtration. The product is Washed with water, dried and recrystallized from ethyl acetate to give Ncarbarnyl-9a, locedifiuoro 11/3,17e-dihydroxy 20 oxo-4,6-pregnadicno- 3,2-c1pyr-azoie.

To a solution or 6 2 mg. of Is-Carbamyl-QaJ6ez-difiuoro 11/3,17ct,21-trihydroxy 20 oxo-4,6-pregnadieno- [3,2-c]pyrazole 2l-mesylatc in 1 ml. of freshly distilled anhydrous dimethylfor-amide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate, and evaporated to dryness. The resulting product is a mixture of N-carbamyl 170:,21 epoxy 9a,l6c: diiluoro-llfi-hydroxy 20 oxo-4,6-pregnadieno-[3,2-cjpyrazole and N- carbam 'l-9cc,21-difiuoro ll/3,l7u dihydroxy 16a methyl 20 oxo-4,6-pregnadiene[3,2-c1pyrazole, which compounds are separated by partition chromatography, or by chromatography on silica gel.

To a solution or" 355 mg. of N-carbarnyl :,160: difiuoro 115,170 dihydroxy 20 oxo-4,6-pregnadieno- [3,2-c]pyrazole in 35 ml. of glacial acetic acid there is added slowl with stirring 104 mg. of sodium nitrite in 5 ml. of W316i. After fifteen minutes at room temperature most of the acetic acid is removed at room temperature on the rotating evaporator. Ethyl acetate is added and this solution is extracted several times with sodium bi rbonate and then dried. Removal or the solvent, followed by chromatography on alumina affords 9a,l6c difiuoro llfl,l7cz dihydroxy 20 oxo-4,6-pregnadieno- [3,2-c1pyrazole.

in accordance with the above procedure, but starting with the N-carbamyl 9a,l6a,2l UiilL1OIOll[i,l7 x-dl hydroxy-ZO-oxo 4,6 pregnadieno-[3,2-c]pyrazole there is obtained the 9a,16a,21-triliuoro-1lfl,17a-dihydroxy-20- oxo-4,6-pregnadieno-[3,2-c1pyrazole.

The N-carbamyl-9u,16e-diiluoro 115,17 dihydroxy 20-oxo 4,6 pregnadieno-[3,2-c]pyrazole Zl-dih-ydrogen phosphate, and the monoand dialkali metal salts thereof, are prepared from the 'N-carbamyl-9rx,loa-difiuoroll ,6,l7z-dihydroxy 21-iodo20-oxo-4,6-pregnadieno-[3,2- clpyrazole following the detailed procedure in column 32, lines 10-46; the N-carbamyl-group is then removed by the above procedure.

Example 6 To a solution of 0.5 millimole of 170:,20,20,Z1-bi5- (methylenedioxy) a fiuoro 11$ hydroxy-Z-hydroxyrnethylene 4 pregnene 3 one (Example 4) in about 3 ml. of absolute ethanol is added 0.6 millimole of sodium acetate and then 0.6 milli-mole of methylhydrazine sulfate. The mixture is refluxed under nitrogen for 40 minutes and then filtered hot. The filtrate is taken to dryness, Water is added, and the 17rx,20,20,21- bis(methylenedioxy) 16m fluoroN-methyl 11,8 hydroxy-4-pregneno-[3,2-c]pyrazole which is formed as the major component is removed by filtration.

Alternately, a mixture of 1'-methyl-, and 2'-methyll7a,20,20,2i-'bis(methylenedioxy) 16a fiuoro 11,8- hydroxy 4 pregneno-[3,2-c]pyrazole is prepared by heating 17a,20,20,2l-bis(methylenedioxy) 16o: fluoro- 11 fi-hydroxy 2 hydroxymethylene 4 pregnene-3-one with methanol in the presence of p-toluene-sulfonic acid to form the 17u,20,20,21-bis(methylenedioxy) 16o; fluoro- 11 fishydrox 2 methox-ymethylene 4 pregnene-Br-one, and then reacting the latter compound with methylhydr-azine, following the detailed procedures given in column 31, lines 423, but using methylhydrazine instead of phenylhydr-azine in the second step of the reaction. The components of the mixture are separated by cinematography.

In accordance with all the above procedures, but using other allcyl substituted hydrazines such as ethyl-, fi-hydroxyethyl-, pro-pyl-, butylh-ydrazines, and the like, in place of methylhydrazine, there are obtained the corresponding 1-alkyland 2-alkyl-17o,20,20,21-bis(methylcnedioxy) 16cc iluoro-l1fi-hydroxyl-pregneno-[3,2-c] pyrazoles.

The 17m,20,20,21-bis(methylenedioxy) IGa-fiuoro-N- methyl 11,6 hydroxy 4 pregne-no-[3,2-c]pyrazoles may be prepared by the following procedure:

The 17a,20,20,2l-bis(methylenedioxy) 16m fluoro- 11 fi-hYdlOXy 2 hydroxymethylene 4 pregnene-3-one is dissolved in 9.2 ml. of absolute ethanol and treated with a solution of 0.16 ml. of hydrazine hydrate dissolved in 0.16 ml. of absolute ethanol. The mixture is refluxed in 2'9 "ogcn atnz e for about 45 minutes and then orated to di ness under reduced pressure. The residue is washed three times with cold water and the resulting amorphous solid is dried at 80 C. for one hour in high vacuum to give Wolf/10,262l-bis(methylenedioxy)- lfiailuoro 116 s regneno-[3,2-c1pyrazolc.

A solution of about 8.47 lriiiilllflifi of 17a,20,20,21-bi$- (niethylenedioxy -16oz-fitl0l'0 11B hydrox -4-pregneno- [3,Z-c1pyrazoie in it) ml. of b uzene is treated with about 3G-38 mg. of about 51% sodium hydride (in oil suspension}. After the addition of 23 ml. of dimethylfornramide (dried over calcium hydride) and 5 ml. of methyl iodide, the mixture is stirred at room temperature over ni ht The product is filtered, Washed with methylene e, and the and washings are taken to dry- "Zhe residue is treated with Water and the product is filtered to a major component the 17a,2tl,20, 21-bis(znethy enedioxy)-l6a-iluoro 11B hydroxy-N- n1ethyl-4-pregneno-[3,2-c1pyrazole.

In accordance w h the above procedure, but using another alleyla g agent, for example, etnyl iodide, propyl iodide the like, in piece of the methyl iodide, there is obtained the corres onding N-alliyl 17c .,20,20,21 bis- (methyleneuioxy) 16a i'luoro 11,8 hydroxy-4-pregnenol 3,2-cl pyrazole.

The l7e,20,2( ,2l-bis(niethylenedioxy)dom-tluoro-l1hzole mg.) is heated on a steam bath with 1 ml. of 60% formic acid for about 20 minutes and then filtered hot. The filtrate is taken to dryness, Water is added, and a mixture of tr e ioct-iluoro 11,8,170621 trihydroxy-Z'-1nethyl-20- oxo-4-pregneno [3,2-clpyrazole and its 21-forrnate is recovered by A 561) mg. aliquot of this crude product is dis ved in 2.4 of pure methanol and ailowed to react 1 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitronosphere for ten m tes. The alkoxide is neul with acetic a. d and the mixture is then taken to dryness and flushed with n-hexane. The residue is Washed with water, filtered and dried to constant weight to give 16a fiuoro l1,8,l7a,2i tril'iydroxyi'-methyl20-oxo-4- pregneno- 3,2-c1pyrazole.

To a solution of 100 of l6wtluoro-11p,i7ct,21-trihydroxy 2 methyl 2D oxo 4 pregame-[33c] pyrazole in 2 fill. of pyridine is added one n'lilliequivalent of acetic anhydride. The mixture is allowed to stand over it ht room to n A mixture of ice and water is standlng for about 30 minutes, the ted with e yl acetate. The ethyl acetate succes y with water, ice-cold 1 N H or? the aqueous layer is 13), in bicarbonate (until the pH of d water (until the aqueous laysur iric at, saturated a the aqueous laye or is neutral). acetate solution is dried with hydrous sow. The solvent is then distilled at about 49' i The len-fluoro-l 1,8,17oz, 2 l -trir roxy oxo-4-pregueno- 3 ,ZE-c] pyrazole 2 -.-acctatc is then isolated by addition of water and filtration.

in accordance with too above procedure, but using an equivalent quantit of ano her acyl .g agent in place of acetic there dined the corresponding 15:!- iluoro 11,8,17e,2l trihyeroxy 2 metityl-ZO-Qxolpregneno-[3,2-c1pyrazole Zl-acylate.

To a solution of 2:5 mg. of 16.1.- rihydr. xy 2 hyl O oxo-e azole in 0.5 ml. of py e, cooled to 0 C., is added 0.615 ml. of methane sulionyl chloride. The resulting mixture is allowed to stand at a temperature of approximately (3 C. for pc d of appro ately 1 hour. Water is added to the re .ction e and the precipitate which forms ecovcrcd by filtration, washed with water,

ted to 16w? oro 11.,d,l7a,21 trihydroxy- 2'-rnethyl 2O oxo 4 prcgneno-[3,Zc]pyrazole 2iinesylate.

gneno- [3,2-cjpyr- To 189 of l6a-fiuoro -11,3,17e,21 trihydroxy- 2-methyl 2i) oxo 4 -pregneno-[3,2-c1pyrazole 2imesylate dissolved in it) ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temp .ture and diluted with Water. The material which precipitates is recovered by filtration, washed with wate and dried to give 16a fluoro 11,8,l7a dihydroxy-Z1-iodo-2-rnethyl- 20-oxo-4-progneno- 3 ,Z-c] pyrazole.

The 16ot-iluoro-115,17a-dihydroxy 21 iodo-2-methyl- 20-oxo-4- regneno-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of Water and 5 ml. of ethanol. To the result ing suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the material which separates is recovered by filtration. The product is washed with Water, dried and recrystallized from ethyl acetate to give 16u-fiuoro- 11B,17u-dihydroxy-Z-rnethyl-20-oxo-4 pregneno [3,2-c] pyrazole.

To a solution of 62 of lu-fiuoro-ll/Llhiltrihydroxy-2'-rnethyl-20 oxol-pregneno [3,2-c1pyrazole ll-mesylate in 1 ml. of freshly distilled anhydrous dimethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of 170:,21- epoxy-16a-fluoro-1ldhydroxy-T-methyl-ZO oxo 4-pregneno-[3,2-c]pyrazole and 16a,2l difluoro 11),17a dil1ydroxy-2',16c dimethyl 20 oxo-4 pregneno [3,2-0] pyrazole, which compounds are separated by partition chromatography, or by chromatography on silica gel.

In accordance with the above procedures beginning with the 2'-methyl 17a,'.ZO,20,2l bis (-methylenedioxy)- 16ca-fluoro-1lfi-hydroxyl-pregneno [3,2-c]pyrazole, but using the l-methyl-derivative in place of the 2'-methylderivative, there are obtained the corresponding 1'-1nethyl compounds.

In accordance with all of the above procedures, but starting with the 17u,20,20,21-bis(methylenedioxy)-16afiuoro-Z-hydroxyrnethylene-4-pregnene-derivativc which is obtained from each of the starting materials which are defined by the Formula 3 there are obtained the corre sponding 1'-rnethyland 2'-rnethyl derivative.

refluxed under nitrogen in 1.2 ml. of absolute ethanol for 50 minutes. The reaction mixture is taken to dryness. Water is added and the product is filtered to give an amorphous solid, which is washed successively witi water, dilute acid, water, and petroleum ether. The product is crystallized from methanol to give 17a,26,20,2.1-bis(methylenedioxy)-16a-iluoro-1lfi-hydroxy Z'-phenyl 4 pregneno-[3 ,2-c] pyrazole.

Alternately, a mixture of the 1-phenyl and 2'-phenyl- 17a,20,2 ),21-bis(niethylenedioxy) 16a luoro 11B hydroxy 4 pregneno [3,2-c1pyrazole is prepared by the following route: A mixture of 1 gram of l7a ,20,20,2lbis(met'nylenedioxy) la-fluoro-l lfi-hydroxy 2 hydroxymethylene-4-pregnene-3-one, 200 ml. of methanol, and 286 mg. of p-toluenesulionic acid is heated to reflux temperature and then allowed to stand at room temperature for one hour. The reaction mixture is then diluted with water and extracted with ethyl acetate. The ethyl acetate extract is Washed two times with 2 N aqueous sodium hydroxide solution and then with water. The ethyl acetate extract is then dried and concentrated under vacuum. The 17 a,20,20,21-bis(methylenedioxy) 16cc fluoro-ll l3- hydroxy-Z-rnethoxymethylene 4 pregnene 3 one is obtained by direct crystallization or by chromatography on acid-washed alumina and elution with ether:chloroform mixtures.

A mixture of 500 mg. of 17a,20,20,2l-bis(methylenedioxy)-l6 x-fluoro-l1B-hydroxy-2 methoxymethylene 4- ;pregnene-3-one, 100 ml. of ethanol, and 1 ml. of phenylhydrazine is heated under nitrogen until dissolved, and then allowed to stand under nitrogen at room temperature over night. Acetic acid (2 ml.) is added and the mixture is allowed to stand for another 4 hours. The reaction mixture is then diluted with ethyl acetate, washed two times with 2 N sulfuric acid, two times with 2.5 N sodium hydroxide, and then two times with water. The ethyl acetate extract is then dried, concentrated, and chromatographed on acid-washed alumina. Elution with benzene affords a product which on recrystallization from a mixture of benzene and ethylene acetate affords the 17a,20,20,21- bis(methylenedioxy) 16a fluoro 11B- hydroxy-1'-phenyl-4-pregneno-[3,2-c1pyrazole. Further elution with a mixture of 1:1 ether: petroleum ether and crystallization from benzene, affords the 17a,20,20,21-bis (methylenedioxy)door-fluoro 11B hydroxy 2' phenyl- 4-pregneno-[3,2-c1pyrazole.

A 30 mg. aliquot of 17a,20,20,2l-bis(methylenedioxy)- l6a-fluoro-l lfl-hydroxy-Z-phenyl 4 pregneno [3,2-c] pyrazole is heated on a steam bath with 2 ml. of 60% 'formic acid for 35 minutes. The solvents are removed under vacuum, water is added and the product is filtered "off to give a mixture of loot-fiuoro-llo,l7ix,2l-trihydroxy- 20-oxo 2-phenyl 4 pregneno [3,2-c1pyrazole and its 2l-formate. The presence of formate is indicated by infrared absorption at 5.81 and 8.5a.

A 500 mg. aliquot of this crude product is dissolved in 2.4 ml. of pure methanol and allowed to react with 0.9 ml. of a 1.33 N solution of sodium methoxide in methanol at room temperature under a nitrogen atmosphere for 10 minutes. The alkoxide is neutralized with acetic acid and the mixture is then taken to dryness and flushed with n-hexane. The residue is washed With water, ailtered and dried to constant weight to give 16oz-fl11010- 1l/3,17cq,2l-trihydroxy-20 oxo 2- phenyl 4 pregneno- ;[3,2-c]pyrazole.

The 160:. fluoro l1p,17a,2l-trihydroxyQ0-oxo-2 lphenyl-4-pregneno-[3,2-c]pyrazole is treated with a mixture of 1.5 ml. of pyridine and 1.5 ml. of acetic anhydride and the mixture is allowed to stand at room tern perature over night. The solvents are removed under vacuum, water is added and the l6e-fluor'o-llfl,l7u,2-ltrihydroxy-Z-O oxo-2'-phenyl-4-pregneno-[3,2-c] pyrazole Ill-acetate is removed by filtration. After drying, the compound is dissolved in methylene chloride, a few drops of 2.5 N HCl are added and the mixture is taken to dryness. The resulting loa-fluoro-llp,17a,21-trihydroxy-ZO oxo-Z'-phenyl-4-pregneno-[3,2-c]pyrazole 21- acetate hydrochloride salt is soluble in methylene chloride and can be crystallized from acetone.

The 160: fluoro l1p,170,21-trihydroxy-20-oxo-2'- phenyl-4-pregneno-[3,2-c1pynazole (100 mg.) is dissolved 1n 1.2 cc. of dimethylformamide. The solution is cooled to 0 C. and 0.07 cc. of methane sulfonyl chloride is added. The mixture is kept at 0 C. for about one :hour, 3 cc. of Water is added and the product is extracted into 100 cc. of chloroform, washed with water, dried over :sodium sulfate and taken to dryness to afford the 160:- 'fluoro-1l5,l7a,21-trihydroxy 20 oxo 2 phenyl-4- pregneno-[3,2-c]pyrazole 21-mesylate.

The 160: fluoro 11,8,l7ot,21-trihydroxy-20-oxo-2'- phenyl-4-pregneno-[3,2-c]pynazole ZI-m'esylate is suspended in 5.5 cc. of acetone and 117 mg. of sodium iodide 13 added. The mixture is refluxed under nitrogen for about one hour. It is then cooled on ice. On the addition of water there is formed a white precipitate which is filtered ofi, Washed with Water, and dried under vacuum to give the 160: fluoro 11fi,l7c dihydroxy-Zl-iodo-ZO- oxo-2'-phenyl-4-pregneno-[3,2-c1pyrazole.

The above material is dissolved in 5 cc. of ethanol. Five hundred mg. of sodium bisulfite in 5 cc. of water is added, and the mixture is refluxed for one hour under nitrogen. Ten cc. of water is then added and the product is extracted into cc. of chloroform, washed with water, dried over sodium sulfate and taken to dryness, to give a residue which is purified by chromatography on silica gel. The l6a.-fluoro-llB,17a-dihydroxy-20-oxo- 2-phenyl-4-pregneno-[3,2-c]pyrazole so obtained is crystallized from acetone-ether.

Silver dihydrogen phosphate is prepared by the reaction of 32 g. of trisilver phosphate with 10 ml. of 100% phosphoric acid with thorough mixing in a onealiter 3- necke'd round-bottomed flask. The silver d-ihydrogen phosphate is washed with two portions of diethyl ether, which are removed by decantation, to remove some of the phosphoric acid. About 200 ml. of acetonitrile are added to cover the silver dihydrogen phosphate, and the mixture is heated to reflux temperature. At this point 20 g. of lfioc-fitlOl'O l1/3,17co'dll1yClIOXy-21l0dO-20-OX0 2-phe nyl-4-pregneno-[3,2-c1pyrazole is added and the mixture is refluxed in a nitrogen atmosphere with stirring for 75 minutes. The reaction mixture is then cooled over a period of about one hour to room temperature. Then 200 g. of ice water are added, and the acetonitrile is removed under vacuum at a tempenature below 25 C. The pH of the resulting aqueous suspension is adjusted to 6.4 by the addition of 23 ml. of saturated aqueous sodium carbonate solution. A precipitate is formed and separated by filtration. The precipitate is Washed with water until no ultraviolet absorbing material is detected in the wash water. The filtrate and wash water are combined and freeze dried to separate -a solid material from the water. The solid material is triturated with a total of 770 ml. of methanol in seven portions. The methanolinsolu-ble material is separated by filtration. The filtrate is then concentrated under vacuum to 200 m1. and passed through a column containing 60 g. of a cation exchange resin (IR-) in its hydrogen form. The column is washed with methanol until the washings contain no ultraviolet absorbing material. The combined eluatie and washings are concentrated to a volume of 15 ml., and ml. of other are added. The precipitate which forms is recovered by filtration, washed with ether, and dried for about 16 hours in a desiccator, to give fiuoro 115,17a dihydroxy-ZO-oxo-2'-phenyl-4-pregneno- [3,2-c] pyrazole 2l-dihydrogen phosphate.

The mono= and the dialkali-met'al salts of the 2l1-dihydrogen phosphate compound are obtained by neutralizing the ZI-dihydrogen phosphate ester with an alkali metal methoxide.

To a solution of 62 mg. of l6o-flu0rO-ll[3,l7oz,2l trihydroxy-Z0-oxo-'2'-phenyi4-pregneno-[3,2 c]pyrazole 2l-mesylate in 1 ml. of freshly distilled anhydrous tlll'll iihylformamide is added enough anhydrous potassium fluoride to assure a satunated solution. The mixture is heated at 110 C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of l7oc,2l-epoxy-l6afluoroJIB hydm-xy 20 oxo 2-phenyl-4-pregneno- [3,2-c1pynazole and 16a,2l-difiuoro-11,8,l7ot-di hydroxy- 20-oxo-2'-phenyl-4-pregneno-[3,2-c]pyrazole, which compounds ane separated by partition chromatography, or by chromatography on silica gel.

In accordance with the above procedures beginning with the 2-phenyl-17a,20,20,2l-bis(methylenedioxy) l6e-fluono-1 lfi-hydroxy-4-pregneno-[3,2-c1pyrazole, but using the 1'-phenyl-derivatives in place of the 2-phenylderivatives, there are obtained the corresponding 1- phenyl-oompounds.

In accordance with all of the above procedures, but starting with the l7a,20,20,2l-bis(methylenedioxy)-16otfluoro-2-hydroxymethylene-4-pregnene derivative which is obtained from each of the starting materials which 33 are defined by the formula in columns 30-3 1, lines 61 and 63, there are obtained the corresponding 1'-phenyland 2-phenyl derivatives.

Example 8 A 111.5 mg. sample of 17u,20,20,21-bis(methylenedioxy) 16a fluoro 11B hydroxy-2-hydroxymethylenelpregnene-3one is suspended in 2.5 ml. of ethanol and treated with 24.5 mg. of sodium acetate, following with the addition of 48.5 mg. of p-iiuorophenylhydrazine hydrochloride. The air in the system is replaced with nitrogen and the mixture is quickly brought to reflux temperature. After refluxing for one hour the mixture is taken to dryness. The residue is dissolved in ether, the ether layer is treated three times with 2.5 N hydrochloric acid, then three times with 2.5 N sodium hydroxide and finally with water. The ether layer is dried over mag esiuin sulfate, filtered and concentrated to dryness under vacuum to give a residue which has as its major component the 17a,20,20,21 bis(methylenedioxy)-l6rx-fiuoro-2-(p-fiuorophenyl) 1lfl-hydroxyl-pregneno[3,2-]pyrazole. The latter compound is recovered by dissolving the reaction mixture in methanol and then recrystallizing.

Alternately, a mixture of the 1-(p-fiuorophenyl)- and the 2 (p fiuorophenyl)-17ct,20,20,21-bis (methylenedioxy) 16et-fiuoro-11fi-hydroxy-4-pregneno[3,2-c1pyrazole is prepared by the following route: A mixture of 1 gram of 17ot,20,20,2l-bis-(methylenedioxy)-l6a-fluoro-llfi-hydrox-2-hydroxymethylene-4-pregnene-3-one, 200 ml. of methanol, and 200 mg. of p-toluenesulfonic acid is heated to reflux temperature and then allowed to stand at room temperature for one hour. The reaction mixture is then diluted with water and extracted with ethyl acetate. The ethyl acetate extract is washed two times with 2 N aqueous sodium hydroxide solution and then with water. The ethyl acetate extract is then dried and concentrated under vacuum. The 17a,20,2t),21-bis(methylenedioxfl-lM-ilnoro-l1p-hydroxy-2-rnethoxymethylene-4-pregnene-3-one is obtained by direct crystallization or by chromatography on acid-washed alumina and elution with etherzchloroform mixtures.

A mixture of 500 mg. of 17a,20,20,21-bis-(methylenedioxy) 16ot-fiuoro-1lfi-hydroxy-16-methyl-2-1nethoxymethylene-4-pregnene-3-one, 100 m1. of ethanol, and 1 ml. of p-fluorophenylhydrazine is heated under nitrogen until dissolved, and then allowed to stand under nitrogen at room temperature over night. Acetic acid (2 ml.) is added and the mixture is allowed to stand for another 4 hours. The reaction mixture is then diluted with ethyl acetate, washed two times with 2 N sulfuric acid, two times with 2.5 N sodium hydroxide, and then two times with water. The ethyl acetate extract is then dried, concentrated, and chromatographed on acid-washed alumina. Elution with benzene affords a product which on recrystallization from a mixture of benezne and ethyl acetate affords the l7a,20,20,2l-bis(methylenedioxy)-16u-fluoro 1' fluorophenyl-l lfl-hydroxyl-pregneno[3,2-c1pyrazole. Further elution with a mixture of 1:1 etherzpetroleum ether, and crystallization from benzene, affords the 17a,20, 20,21 bis (methylenedioxy) -1 6a-fluoro-2'-(p-fluorophenyl)-4-pregneno-[3,2-c1pyrazole.

A 70 mg. aliquot of 17a,20,20,21-bis(methylenedioxy)- 160a fiuoro-2'-(p-fluorophenyl)11/3-hydr0xy-4-pregneno- [3,2-c1pyrazole is heated on a steam bath with 2 ml. of a 60% solution of formic acid for 35 minutes. The excess reagent is removed under vacuum using a water bath at about 50 C. The residue is thoroughly washed with water and then dried at 80 C. to give 61.1 mg. of residue. The crude product is dissolved in 3 ml. of spectral grade methanol and allowed to react with 0.5 ml. of a 0.1 N solution of sodium methoxide in methanol at room temperature for minutes. The product is neutralized with acetic acid. The mixture is then taken to dryness and washed thoroughly with water, filtered and dried to constant weight to give 1lB-17 z,21-trihydroxy-16a-fiuoro-2- (p-fiuorophenyl)-20-oxo-4-pregneno-[3,2c]pyrazole.

To a solution of mg. of 16a-fiuoro- 2'-(p-lluorophenyl) 1 15-,170:,21-trihydroxy-2O-oxo-4-pregneno-[3,2- c]pyrazole in 2 ml. of pyridine is added one milliequivalent of acetic anhydride. The mixture is allowed to stand over night at room temperature. A mixture of ice and water is then added. After standing for about 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate extract is washed successively with water, ice-cold 1 N sulfuric acid (until the pH of the aqueous layer is 1-3), saturated aqueous sodium bicarbonate (until the pH of the aqueous layer is 8), and water (until the aqueous layer is neutral). The ethyl acetate solution is dried with anhydrous sodium sulfate. The solvent is then distilled at about 40 C. under vacuum to afford 16cz-fiuoro-11 3,17 21 trihydroxy-2'-(p-fiuorophenyl )-20-oxo-4-pregneno- [3 2-c]pyrazole 21-acetate which is isolated by the addition of water and filtration. After drying, the compound is dissolved in methylene chloride, a few drops of 2.5 N HCl are added and the mixture is taken to dryness. The resulting hydrochloride salt is crystallized from acetone.

The 21-dihydrogen phosphate esters and the monoand dialkali metal salts thereof are prepared by the procedure given in detail in column 32, lines 10-46 for the corresponding 2-phenyl-steroid.

In accordance with the above procedure, but using an equivalent quantity of another acylating agent in place of acetic anhydride, there is obtained the corresponding 2l-acylate.

To a solution of 85 mg. of 2"-(p-iluorophenyl)-16afluoro-11,8,17a,2l trihydroxy-20-oxo-4-pregneno-[3,2-c] pyrazole in 0.5 ml. of pyridine, cooled to 0 C. is added 0.015 ml. of methanesulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the crystalline precipitate which forms is recovered by filtration, washed with water, and dried to give 16ailuoro-2-(pfiuorophenyl)-11fl,l7a,21 trihydroxy-ZO-oxo-4-pregneno- [3,2-c1pyrazole 21-rnesylate.

To 180 mg. of 16ot-fluoro-2'-(p-fluorophenyl)-11f3,l7a, 21-trihydroxy-20-oxo 4 pregneno-[3,2-c1pyrazole 21- rnesylate dissolved in 10 ml. of acetone is added 300 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The crystalline material which precipitates is recovered by filtration, Washed with water, and dried to give 16a-lluOro-2'-(p-fluorophenyl)--115,170:- dihydroxy-Z1-iodo-20-oxo-4-pregneno-[3,2-c]pyrazole.

The l6a-iluoro-2-(p-fluorophenyl) -l l/3,l7u-dihydr0xy- 21-iodo-20-oxo-4-pregneno-[3,2-c]pyrazole is dissolved in a mixture of 5 ml. of water and 5 ml. of ethanol. To the resulting suspension is added 500 mg. of sodium bisulfite, and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with water, and the crystalline material which separates is recovered by filtration. The product is washed with water, dried and recrystallized from ethyl acetate to give 16a-liuoro-2-(p-fiuorophenyl)-115,17a dihydroxy 20- oxo-4-pregneno-[3,2-c1pyrazole.

To a solution of 62 mg. of lfict-fiuoro-T-(p-fiuorophenyl)-11/3,170:,21-trihydroxy-20-oxo-4 pregneno-[3,2- cfjpyrazole 21-mesylate in 1 ml. of freshly distilled anhydrous dirnethylformamide is added enough anhydrous potassium fluoride to assure a saturated solution. The mixture is heated at C. for 20 hours. Water is added to the cooled solution and the product is extracted into chloroform, dried over sodium sulfate and evaporated to dryness. The resulting product is a mixture of 2 p-fiuorophenyl)-17a,21-epoxy 16v. fiuoro-llfl-hydroxy-ZO-oxo-4-pregneno [3,2-c1pyrazole and 2'-(p-fluorophenyl)-16a,2l-difluoro-11 [5,170t-(lii1Yd1OXY-ZO oxo-4- pregneno-[3,2-c]pyrazole which compounds are separated by partition chromatography.

In accordance with the above procedures beginning with the 16a-iluoro-2'-(p-fiuorophenyl)-l7a,20,20,2l-bis (methylenedioxyyllfi hydroxy-4-pregneno-[3,2-c]pyrazole, but using the 1'-(pluorophenyl)-derivative in place of the 2-(p-fluorophenyl)-derivative, there are obtained the corresponding l'-(p-luorophenyl)-comp0unds.

in accordance with .all of the above procedures, but starting with the 17a,20,20,2l-bis(-methylenedioxy)-2-hydroxymethylene-4-pregnene-derivative which is obtained from each of the starting materials which are defined by the formula on page 3 there are obtained the corresponding 1-(p-fiuorophenyl)- and 2-(p-iluorephenyl}-dcrivatives.

Example 9 One gram of methyl 3,1l-dileto-4,17(20)-pregnsdiene- Zl-oate is dissolved in 10 ml.-of absolute ethanol and 2 ml. of ethyl orthoformate. Fifty milligrams of 2,4-dinitrobenzenesulfonic acid is added and, after stirring at room temperature for forty-five minutes, the reaction mixture is neutralized With pyridine and taken to dryness finally under high vacuum. The crude residual 3-enol ethyl ether is of sufficient purity for the next step.

Example 10 Two hundred and fifty milligrams of the 3-enol ethyl ether of methyl 3,1l dilcetol,l7(20)-pregnadiene-2loate is dissolved in 5 ml. of dry pyridine. This mixture is cooled to 20 C. and perchloryl fluoride is bubbled through slowly for three minutes. it is then poured into ice and Water and extracted several times with ethyl acetate. The organis layer is Washed first With dilute hydrochloric acid and then with 5% sodium bicarbonate, and then dried. The esidue, after removal of solvent, is a mixture of the 6st and 6fi-tluoro-isomers and is used in the next step Without purification.

Example 11 Three hundred and eighty-five milligrams of the crude 3-enol ethyl ether of methyl 3,11-diketo-4,l7(20)-pregnadiene-Zl-oate is dissolved in 10 ml. of acetone containing 0.17 g. of sodium acetate dissolved in 1.7 ml. of Water and the mixture is cooled to 0 C. N-chlorosuccinirnide (170 mg.) is added, immediately followed by 0.17 ml. of glacial acetic acid. The reaction mixture is stirred in the ice bath for one and one-half hours and is then poured into ice Water and extracted into ethyl acetate. Removal of the dried solvent leaves a residue containing methyl-6,6-chloro-3,1l-diketo 4,l7(20)-pregnadiene 21- oate which is used directly in the next step.

Example 12 Two hundred inillignams of the crude methyhg-fiuoro- 3,11-diketo-4,17(20)-pre-gnadiene-21-oate are refluxed in a. Dean-Stark Water separator in 10 ml. of benzene with 0.5 ml. of pyrroi-dine and 50 mg. of p-toluenesulfonic acid. After twenty-four hours, the cooled reaction mixture is extracted rapidly once With Water, dried and taken to dryness. The residue is redissolved in 10 ml. of tetrahydrofuran, 200 mg. of lithium aluminum hydride are added and the mixture is refluxed for two hours. Water is cautiously added lo the cooled reaction mixture, followed by ethyl acetate. The organic layer is separated and taken to dryness. The residue is refluxed for four hours with 0.75 g. of sodium acetate, 1 ml. of Water, 0.4 ml. of glacial acetic acid and 10 ml. of methanol. Ethyl acetate and water are added and the separated and dried organic layer is taken to dryness. The residue is then treated With 1 ml. of acetic anhydride and 1 ml. of pyridine for eighteen hours at room temperature. Removal of these reagents under vacuum and chromatography on neutral alumina alfords 6a-tluoro-11fi,21-dihydroxy-4, 17 (20) -pregnadiene-3-one 21-acetate.

In accordance with the above procedure but starting with the crude methyl 6 chl0r,o-3,11-diketo-4,17(20)- pregnadiene-Zl-oate, the 6a-chloro-115,2-dihydroxy-4, 17(20)-pregna:diene-3-one 21-acetate is obtained.

Example 13 graphed on silica gel to afford ZI-acetoxy-l1,8,16ot-dihydroxyl, 17 (20) -pregnadiene-3-one.

Example 1 4 A solution of 21-acetoxy-1lfl,16ot-dihydroxy-4,17(20)- pregnadiene-3-one (400 mg.) in 10 ml. of ether and 1 ml. of tributylamine is treated with 0.2 m1. of thionyl chloride. After ten minutes, the solution is poured into iced sodium dihydrogen phosphate and extracted with ethyl acetate. Removal of the dried solvent leaves a residue which contains 20 chloro-Zl-acetoxy-l1fi-hydroxy-4,16- pregnadiene-3-one. This is dissolved in 10 ml. of ethanol to Which 1 N sodium chloride is added dropwise until alkalinity persists over a period of ten minutes. Then acetic acid is carefully added to neutrality and the so vent is removed in vacuo. The residue is dissolved in ethyl acetate, Washed wish Water, and chromatographed on silica gel to afiord 20,2l-epoxylfi-hydroxy-4,16-pregnadiene-3-one.

Example 15 To a solution. of 200 mg. of 20,21-epoxy-11e-hydroxy- 4,l6-pregna.diene-3-one in 2 ml. of chloroform and 2 ml. of tetrahydrofuran in a polyethylene bottle at 60 C. is added 2 ml. of 2:1 (by Weight) m xture of anhydrous hydrogen fluoride and tetrahydrofuran. After 4 hours at l0 C. the mixture is cooled to 60 C. and cautiously added to a stirred mixture of 30 ml. of 25% aqueous potassium carbonate and 25 ml. of chloroform kept at 5 C. The aqueous phase is further extracted with chloroform and the combined organic solvent is washed With sodium bicarbonate and dried. The residue after removal of solvent is treated at room temperature with one ml. of acetic anhydride and one ml. of pyridine. The reaction mixture is taken to dryness under high vacuum on a rotating evaporator and chromatographed on neutral alumina to afford 2l-acetoxyl6c .-fiuoro-llfi-hydroxy-4, 17 (20) -pregnadiene-3 -one.

Example 16 A solution of 325 mg. of 2l acetoxy-l6wlutoro-l1,8- hydroxy-4,17(20)-pregnadiene-3-one is prepared in 10 ml. of t-but anol, 3 ml. of methylene chloride and 0.4 ml.

pyridine. To the solution is added 1.1 ml. of a solutron of N-rnethylmzorpholine oxide-hydrogen peroxide complex in t-butanol. A milligram of osmium tetroxide is added and the solution is stirred at room temperature overnight. Excess reagent is then destroyed by stirring the solution vi orously with aqueous sodium hydrosulfite. After filtration, the organic layer is Washed With aqueous sodium dihydrogen. phosphate and water, dried and removed under vacuum. Chromatography on. Florisil affords l6a-fluoro-115,17s-dihydroxy 21 acctoxyl-pregnene-3,20-dione. Florisil is an activated magnesium silioate made according to U.S. Patent 2,393,625.

The N-rnethylmorpholine oxide-hydrogen peroxide is prepared by the following procedure: T o a solution of 26 grams (0.25 mole) of N-niethylmorpholine in milliliters of tertiary butyl alcohol is added 34 grains (0.50 mole) of fifty percent hydrogen peroxide portionwise, with stirring, and while maintaining the reaction temperature at between thirty and 35 degrees Centigrade with water bath. The resulting solution is then diluted to 170 millimeters with tertiary butyl alcohol, maintained at room temperature for 48 hours, and then dried with sixty grams of anhydrous magnesium sulfate for an additional 24 hours. The magnesium sulfate is removed by filtration and the filtrate is distilled to dryness to produce crystalline N-methylmorpholine peroxide. Alternatively, the solution can \be titrated for available peroxide and the N-methyl-morphol-ine oxide peroxide used without isolation.

Example 17 Five hundred milligrams of 2l-acetoxy-l6a-fluoro-11,6,- 17m dihydroxy-4-pregnene-3,20-dione is dissolved in a mixture of 5 ml. of benzene and 5 ml. of l N-rnethanolic potassium hydroxide and the solution is allowed to stand at room temperature for ten minutes. The solution is then acidified with acetic acid, diluted with ethyl acetate and washed with water. Removal of the dried solvent leaves a residue of 16ctlluoro-llfi,17a,21-trihydroxy-4- pregnene-3,20-dione. This is stirred at room temperature for 70 hours with a mixture of 18 ml. of chloroform, 5 ml. of concentrated hydrochloric acid and 5 ml. of 37% formaldehyde. The chloroform layer is separated and the aqueous layer is extracted several more times with chloroform. The combined organic solvent is washed .with aqueous sodium bicarbonate and dried. Removal of the solvent leaves a residue containing l7a,20,20,2lbismethylenedioxy 1600 fiuoro-4-pregnene-3,20-dione which is further purified by crystallization from methanol.

Example 18 A suspension of 17a,20,20,2l -bis(methylenedioxy)- l6a-fluoro-4-pregnene-3,20-dione (11.1 g.) and chloranil (24.3 g.) in 360 ml. of dry t-butanol is heated under reflux for three hours, protected by a blanket of nitrogen. The solvent is removed and the residue is dissolved in chloroform. The resulting solution is Washed successively with 10% aqueous sodium bisulfite solution, 5% potassium hydroxide, and then water. The solution is dried over sodium sulfate and concentrated under reduced pressure to give 17s,20,20,21-bis(methylenedioxy)-16otfiuoro-4,6-pregnadiene-3,ZO-dione.

Alternately, the 17 a,20,20,21-bis(methylenedioxy)46afiuoro-4,6-pregnadiene-3,20-dione may be prepared by reaction of the 21-acetoxy-16a-fiuoro-1lp,17a-dihydroxy-4- pregnene-3,20-dione with chloranil according to the above reaction, and then treatment of the resulting 21acetoxy- 160a fluoro 11,8,170: dihydroxy-4,6-pregnadiene-3,20 dione first with methanolic potassium hydroxide, and then with formaldehyde in the presence of concentrated HCl using the procedure of Example 17.

In accordance with the procedures of Example 12 through 18 but starting in Example 12 with the 6u-methyl- 2 l -acetoxy-l 1,8-hydroxy-4,l7 (20) -pregnadiene-3-one, 6achloro-Zl-acetoxy-l1B-hydroxy-4,17(20) pregnadicne-3- one or the 6a-iiuoro-21-acetoxy-11[3-hydroxy-4,17(20)- pregnadiene-3-one, or the M -analogues thereof, there are obtained the 6m-methyl, 6ot-chloro and 6a-i'luoro-17a,20,- 20,21 bis(rnethylenedioxy)-l6a-fluoro-4-pregnene 3,20- dione and the corresponding a -analogues thereof.

Example 19 The 6 halo-l6zx-fluoro-11B,l7er-dihydroxy-4,6-pregnadiene-3,20-dione compounds used as starting materials in Example 2 are alternately prepared by the following procedures. (See Flow Sheet C.)

ll-ketoprogesterone (10 g.) and chloranil g.) are refluxed in 350 ml. of dry t-butanol for three hours. The residue after removal of the solvent is dissolved in chloroform and extracted thoroughly with 10% aqueous sodium bisulfite, 5% potassium hydroxide and finally U water. Removal of the dried solvent and chromatography on neutral alumina affords 6-dehydro-ll-ketoprogesterone.

A solution of 3.25 g. of 6-dehydro-ll-ketoprogesterone in 325 ml. of methylene dichloride is cooled in an ice bath and treated with 75 ml. of 1.5 N ethereal monoperpht lic acid an allowed to stand over night at room temperature. The mixture is poured into excess sodium bicarbonate, and the organic layer is separated and dried. Removal of solvent and crystallization from a suitable solvent aifords afla-oxido-ll-l;etoprogesterone.

6a,7 x-oxido-1l-ketoprogesterone (1.0 g.) in 7.5 ml. of glacial acetic acid is saturated at room temperature with anhydrous hydrogen chloride and allowed to stand for four hours at room temperature. It is then poured into Water, extracted with chloroform and washed with water and sodium bicarbonate. Removal of the dried solvent and chromatography on neutral alumina affords 6-chloro- G-dehydrol l-ketoprogesterone.

6a,7 x-oxido1l-ketoprogesterone (1.25 g.) is dissolved in 30 ml. of chloroform and treated with 12.5 ml. of a solution prepared from 7 parts of tetrahydrofuran, 4 parts of chloroform and 4 parts of anhydrous hydrogen fiuoride. After three days at room temperature, the mixture is cautiously poured into iced potassium carbonate and extracted several times witlrchloroforrn. The organic layer is separated, dried and removed. The residue is taken up in 20 ml. of glacial acetic acid and 5 ml. of glacial acetic acid saturated with hydrogen fluoride gas is added. After one hour at room temperature, this mixture is poured into ice and water and extracted with ethyl acetate. After water and sodium bicarbonate washes, the dried solvent is removed and the residue is chromatographed on neutral alumina to allord 6-fiuoro-6-dehydro- 1 l-ketoprogesterone.

A solution of 9.0 g. of 6-chloro-6-dehydro-1l-ketoprogesterone is prepared in ml. of anhydrous t-butanol. To it is added with stirring 13.6 ml. of ethyl oxalate and 25 ml. of 2.5 N sodium methoxide in methanol at about 50 C. This mixture is stirred under nitrogen at room temperature over night. Then 3.06 g. of sodium acetate and 3.53 ml. of glacial acetic acid in 200 ml. of methanol are added. This solution is cooled in an ice bath and 10.8 g. of bromine in 110 ml. of methanol is added slowly over a half hour period. Then 57 ml. of 2.5 N methanolic sodium methoxide is added and the solution is stirred for five hours at room temperature. The mixture is then poured into water and the precipitate is filtered oil and dried. Five grams of this material is dissolved in 100 ml. of benzene, 50 ml. of methanol and 10 ml. of glacial acetic acid. Five grams of zinc dust is added and the reaction mixture is stirred vigorously for four hours. The solids are filtered off and washed with ethyl acetate. The combined organic layer is extracted with dilute sodium bicarbonate and dried. Chromatography on silica gel affords methyl 6-chloro-3,l1-diketo- 4,6,17(20)-pregnatriene-21-oate.

The above compound is then converted into 21-acetoxy- 6 chloro l1fi,21 dihydroxy 4,6,17(20) pregnatriene-3-one following in sequence the procedures of Examples 9 to 18, for the preparation of the corresponding A compounds.

The 21-acetoxy compound may be converted into the corresponding 2l-hydroxy compound using sodium methoxide in methanol following the procedure of page 63.

Example 20 The 21 acetoxy 905,115 dichloro 16a fluoro- 17u-hydroxy-4-pregnene-3,20-dione compounds and the 21 acetoxy 9a,l1B dichloro 16oz fiuoro 6 methylhydroxy 4,6 pregnadiene 3,20 dione compounds used as starting materials in Examples 3 and 4 are prepared, starting with the 21-acetoXy-l6a-fluoro-115,170:- dihydroxy-4-pregnene-3,20-di0ne or the 2l-acetoxy-16ufluoro 11fi,17a dihydroxy 4,6 pregnadiene 3,20-

39 dione, in accordance with the following procedures. (Compare Flow Sheet D.)

A solution of 400 mg. of 21-acetoxy-16ot-fluoro-11e, 17cc dihydroxy 6 methyl 4,6 pregnadiene 3,20- dione in 2.0 ml. dimethyl formamide, 0.8 ml. of pyridine and 0.4 ml. of methanesuifonyl chloride is allowed to stand at 75 C. for one hour. The mixture is cooled and Water is added. The precipitate formed is filtered, washed with Water, dried in air and purified by chromatography on alumina and elution with benzene. rystallization gives ZI-acetoxy 16a fluoro-17ot-hydroxy-6 methyl- 4,6,9 1 1 )-pregnatriene-3,20-dine.

N-chlorosuccinimide (160 mg.) is added to a solution of 21 acetoxy 16m fluoro 17a hydroxy 6 methyl- 4,6,9(11)-pregnatriene-3,20-dione (415 mg.) in 25 ml. of glacial acetic acid containing 2 g. of lithium chloride and 125 mg. of dry hydrogen chloride in one-half ml. of tetrahydrofuran. This solution is stirred in the dark for twenty minutes, washed with ice-Water and dilute sodium bicarbonate, dried and then taken to dryness under vacuum. Chromatography on neutarl alumina affords 21 acetoxy 902,11,8 dichloro 16cc uoro 17a hydroxy-6-methyl-4,6-pregnadiene-3,20-dione.

Example 21 The 21 acetoxy 90:,16u difiuoro 11,8,17a dihydroxy-4-pregnene-3,20-dione compounds and the 21- acetoxy 90;,16a difluoro llfi,17ot dihydroxy 4,6- pregnadiene-3,20-dione compounds used as starting mate rials in Example 5 are prepared in accordance with the following procedures.

A solution of 400 mg. of 2l-acetoxy-l6a-fluoro-l1e, 17a dihydroxy 4 pregnene-3,20-dione in 2.0 ml. dimethyl formamide, 0.8 ml. of pyridine and 0.4 ml. of methanesulfonyl chloride is allowed to stand at 75 C. for one hour. The mixture is cooled and water is added. The precipitate formed is filtered, washed with Water, dried in air and purified by chromatography on alumina and elution with benzene. Crystallization gives 21-acetoxy 16a fiuoro 17a hydroxy 4,9(11) pregnadiene-3,20-dione.

To a mixture of 620 mg. of 21-acetoxy-16a-luoro-17ahydroxy-4,9(11)-pregnadiene-3,20-dione and 330 mg. of N-bromosuccinimide in ml. of dioxane, and 3.2 ml. of water cooled to 10 C. is added 1.8 ml. of cold 1 M aqueous perchloric acid. The mixture is stirred at 15 C. for 3 hours. Excess N-bromosuccinimide is destroyed by addition of aqueous sodium thiosulfate and most of the dioxane is removed under vacuum. About 30 ml. of water is added and the product is filtered, washed with Water, and dried in air to give 2l-KCfitOXY-90t-bl0lIIO-l6ocfluoro-l 1p,17a-dihydroxy-4-pregnene-3,20-dione.

A solution of 210 mg. of 21-acetoxy-9ct-bron1o-l6ctfluoro-l118,17wdihydroxy-4-pregnene-3,20-dione and 240 mg. of potassium acetate in 10 ml. of absolute ethanol is heated under refiux for two hours. The reaction mixture is cooled to room temperature, and evaporated under vacuum to a small volume. The concentrated aqueous mixture is extracted with three portions of ethyl acetate, and the combined ethyl acetate extracts are washed with water, dried, and evaporated to dryness under vacuum. The residual material is crystallized from a mixture of ethyl acetate and ether to give 21-acetoxy-9ot,11fi-epoxy- 16a-tluoro-17a-hydroxy-4-pregnene-3,20-dione.

To a solution of 200 mg. of 21-acetoxy-9a,115-epoxy- 16a-flu oro-17a-hydroxy-4-pregnene-3,20 dione in 2 ml. of chloroform and 2 ml. of tetrahydrofuran in a polyethylene bottle at'60 C. is added 2 ml. of a 2:1 (by weight) mixture of anhydrous hydrogen fluoride and tetrahydrofuran. After 4 hours'at 10 C. the mixture is cooled to -60 C. and cautiously added to a stirred mixture of 30 ml. of 25% aqueous potassium carbonate and 25 ml. of chloroform kept at 5 C. The aqueous phase is further extracted with chloroform and the latter phase is washed With Water and dried over magnesium sulfate.

The residue on crystallization from a mixture of acetone and ether gives 21-acetoxy-9a,Ida-difluorO-l1/8,17a-dihydroxy-4-pregnene-3,20-dione.

A suspension of 21-acetoxy-9a,l6a-difluoro-11,8g17adihydroxy-4-pregnene-3,20-dione (1 1.1 g.) and chlonanil (24.3 g.) in 360 ml. of dry t-butanol is heated under reflux for three hours, protected by a blanket of nitrogen. The solvent is removed and the residue is dissolved in chloroform. The resulting solution is washed successively with 10% aqueous sodium bisulfite solution, 5% potassium hydroxide, and then water. The solution is dried over sodium sulfate and concentrated under reduced pressure to give 21a-acetoxy-9a,16a-difiuoro-11,B,17t-dihydroxy-4,6-pregnadiene-3,20-dione.

Example 22 The 9a,1 le-dichloro-16tx-fiuoro-17a-hydroxy-20-oxo-4- pregneno-[3,2-c]pyrazole (37.3 mg.) is treated with 3 ml. of acetic anhydride and 1 ml. of a solution of 304 mg. of p-toluenesulfonic acid monohydrate dissolved in 10 ml. of acetic anhydride. The mixture is kept at room temperature for 20 hours. The solvent is removed under vacuum. The residue is dissolved in 1 ml. of ether which has been washed once with 1 ml. of Water. The aqueous phase is back-extnacted twice with 1 ml. of ether. The combined ethereal extracts are washed once with 2 ml. of 10% sodium bicarbonate solution. The aqueous phase is then back-extracted With 1 ml. of ether. The combined ether extracts are washed with 1 ml. of water. The aqueous extract is back-extracted with 1 ml. of ether. The combined ethereal extracts are dried over magnesium sulfate, filtered and the solvent removed on a steam bath to give 17a-acetoxy-9a,1lfl-dichlorod6a-fluoro-20-oxo-4- pregneno- 3,2-c] pyrazole N-acetate.

The 17a acetoxy-9u,l 1 fl-dichloro-16u-fluoro-20-oxo-4- pregneno'-[3,2-c]pyrazole N- acetate is dissolved in 3.0 ml. of methanol and treated with 0. 13 ml. of 0.1 N sodium hydroxide. The mixture is heated at reflux temperature for 30 minutes. The solvent is removed on a steam bath to give a crude product which is treated with 1 ml. of water and then extracted with 1 ml. of ether. The layers are separated and the aqueous phase is back extracted three times with 1 ml. of ether. The combined ether extracts are Washed with 1 ml. of water. The organic phase is dried over magnesium sulfate, filtered and the solvent removed. The product is crystallized from methanol to give 23.0 mg. of 17a-acetoxy-9ot,11,8-dichloro-16u-fluoro- 20-oxo-4-pregneno-[3,2-c]pyrazole.

In accordance with the above procedure, but starting with the 17o.-hydroxy-9a,11ti-diohlorod6a-fiuoro-20-oxo- 4,6-pregnadieno-[3,2-c]pyrazole the 17a-acetoxy-9a,11,B- dichl-oro-16a-flu0ro 20 oxo-4,6-pregnadieno-[3,2-c1pyrazole is obtained.

Various changes and modifications may be made in carrying out the present invention Without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of our invention.

We claim:

1. A compound selected from the group consisting of compounds having structural formulas A and B: 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING STRUCTURAL FORMULAS A AND B: 